Skeletal muscle protecting agent

ABSTRACT

The present invention provides a novel drug which is useful as a skeletal muscle protecting agent comprising a compound having inhibitory activity against squalene synthase or a salt thereof, or a prodrug thereof.

TECHNICAL FIELD

The present invention relates to a skeletal muscle protecting agentcomprising a compound having inhibitory activity against squalenesynthase or a salt thereof, or a prodrug thereof.

BACKGROUND ART

The skeletal muscle is an important muscle which is attached to the boneand involved in exercise of the body, but necrosis or myolysis of theskeletal muscle occurs by various factors, for example, ischemia, labor,excessive exercise, trauma (bruise, skeletal muscle bleeding, electricshock), burn, malignant hyperthermia, malignant syndrome, metabolicmyopathy, inflammatory myopathy, muscular dystrophy, infection,poisoning, abnormal metabolism, hyperthermia and the like. Further,myalgia may occur by toxicity of drugs, for example, HMG-CoA reductaseinhibitors, cyclosporin, fibrates and the like, and if it becomesserious, rhabdomyolysis is developed. In such case, administration ofthe medicine which is considered to be causal is stopped, andmaintaining the rest, enough fluid replacement is carried out. There isno effective treatment for muscular lesion, and treatment for thecomplication or fundamental disease is the focus.

On the other hand, it has been known that a compound having inhibitoryactivity against squalene synthase is useful as a preventive and/ortherapeutic agent for hyperlipidemia or atherosclerosis and the like, atriglyceride-lowering agent, a lipid-lowering agent, a high densitylipoprotein cholesterol-elevating agent, an antifungal agent and thelike (JP-A Nos. 6-239843, 8-157369, 9-136880, 2002-080468, and2002-205956). For the action for the skeletal muscle, there has beenonly a report that the cytotoxicity is less likely to be manifested thanthat of the HMG-CoA reductase inhibitor (Oliver P. Flint et al), pp.91-98, Vol. 145, “Toxicology and Applied Pharmacology”, 1997), but noreport that they show protecting action for the skeletal muscle in vitroor in vivo. Further, it has been known that a compound having inhibitoryactivity against squalene synthase increases ubiquinone (WO03/002147),but it has been shown that muscular toxicity of HMG-CoA reductaseinhibitor has nothing to do with ubiquinone (William H. Schaefer et al,doi:10.1016/j.taap. Aug. 13, 2003 “Toxicology and AppliedPharmacology”).

OBJECTS OF THE INVENTION

A medicine which can protect the skeletal muscle from various factors,particularly, from cytotoxicity of an HMG-CoA reductase inhibitor hasnot been known so far. Then, at present, it is desired to develop anovel medicine which is clinically useful.

DISCLOSURE OF THE INVENTION

Under the above circumstances, the present inventors have studiedintensively, and as a result, found unexpectedly for the first time thata compound having squalene synthase inhibitory activity is clinicallyuseful as a medication for protecting the skeletal muscle, whichresulted in the completion of the present invention.

That is, the present invention relates to:

-   -   (1) A skeletal muscle protecting agent comprising a compound        having inhibitory activity against squalene synthase or a salt        thereof, or a prodrug thereof;    -   (2) The agent as described in the above-mentioned (1) which is a        skeletal muscle protecting agent which protects skeletal muscle        from cell disorder;    -   (3) The agent as described in the above-mentioned (1) which is a        skeletal muscle protecting agent which protects skeletal muscle        from cytotoxicity of other medicines;    -   (4) The agent as described in the above-mentioned (3), wherein        the other medicine is an HMG-COA reductase inhibitor;    -   (5) The agent as described in the above-mentioned (1) which is a        preventive and/or therapeutic agent for myalgia or        rhabdomyolysis;    -   (6) The agent as described in the above-mentioned (1), wherein        the compound having inhibitory activity against squalene        synthase is a compound represented by the formula:        wherein R₁ is a hydrogen atom or an optionally substituted        hydrocarbon group, R₂ and R₃ are the same or different and a        hydrogen atom, an optionally substituted hydrocarbon group or an        optionally substituted heterocyclic group, X′ is a substituent        comprising an optionally esterified carboxyl group, an        optionally substituted carbamoyl group, an optionally        substituted hydroxy group, an optionally substituted amino group        or an optionally substituted heterocyclic residue having a        hydrogen atom which can be deprotonated, Ring A is an optionally        substituted benzene ring or an optionally substituted        heterocyclic ring, Ring J′ is a 7- or 8-membered heterocyclic        ring having 3 or less hetero atoms, as atoms constituting a        ring, and Ring J′ may further have a substituent in addition to        R₁, R₂, R₃ and X′;    -   (7) The agent as described in the above-mentioned (1), wherein        the compound having inhibitory activity against squalene        synthase is a compound represented by the formula:        wherein R₁ is a hydrogen atom or an optionally substituted        hydrocarbon group, R₂ and R₃ are the same or different and a        hydrogen atom, an optionally substituted hydrocarbon group or an        optionally substituted heterocyclic group, X₁ is a bond or        divalent atomic chain, Y is an optionally esterified carboxyl        group, an optionally substituted carbamoyl group, an optionally        substituted hydroxy group, an optionally substituted amino group        or an optionally substituted heterocyclic residue having a        hydrogen atom which can be deprotonated, and Ring B is an        optionally substituted benzene ring;    -   (8) The agent as described in the above-mentioned (1), wherein        the compound having inhibitory activity against squalene        synthase is a compound represented by the formula:        wherein R_(b) is a lower alkyl group optionally substituted with        an optionally substituted hydroxy group, X_(b) is an optionally        substituted carbamoyl group or an optionally substituted        heterocyclic group having a hydrogen atom which can be        deprotonated, R_(1b) is a lower alkyl group and W is a halogen        atom;    -   (9) The agent as described in the above-mentioned (8), wherein        R_(b) is C₁₋₆ alkyl which may have 1 to 3 substituents selected        from a hydroxy group, acetyloxy, propionyloxy,        t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and        2-aminopropionyloxy;    -   (10) The agent as described in the above-mentioned (8), wherein        R_(1b) is methyl;    -   (11) The agent as described in the above-mentioned (8), wherein        W is a chlorine atom;    -   (12) The agent as described in the above-mentioned (8), wherein        X_(b) is a group represented by the formula:        wherein R_(2b) and R_(3b) are each a hydrogen atom, an        optionally substituted hydrocarbon group, an optionally        substituted heterocyclic group or an acyl group, or R_(2b) and        R_(3b) may form, together with the adjacent nitrogen atom, an        optionally substituted 5- or 6-membered nitrogen-containing        heterocyclic ring which may contain 1 to 3 hetero atoms selected        from a nitrogen atom, a sulfur atom and an oxygen atom, as atoms        constituting a ring;    -   (13) The agent as described in the above-mentioned (8), wherein        X_(b) is a group represented by the formula:        wherein R″ is a hydrogen atom or C₁₋₄ alkyl;    -   (14) The agent as described in the above-mentioned (1), wherein        the compound having inhibitory activity against squalene        synthase is a compound represented by the formula:        wherein R^(1c) is an optionally substituted 1-carboxyethyl        group, an optionally substituted carboxy-C₃₋₆ straight-chain        alkyl group, an optionally substituted C₃₋₆ straight-chain        alkyl-sulfonyl group, an optionally substituted (carboxy-C₅₋₇        cycloalkyl)-C₁₋₃ alkyl group, or a group represented by the        formula —X^(1c)—X^(2c)—Ar—X^(3c)—X^(4c)—COOH (wherein X^(1c) and        X^(4c) are each a bond or an optionally substituted C₁₋₄        alkylene group, X^(2c) and X^(3c) are each a bond, —O— or —S—,        and Ar is an optionally substituted divalent aromatic cyclic        group, provided that X^(2c) is a bond when X^(1c) is a bond and        X^(3c) is a bond when X^(4c) is a bond), R^(2c) is a C₃₋₆ alkyl        group optionally substituted with an alkanoyloxy group and/or a        hydroxy group, R^(3c) is a lower alkyl group and W is a halogen        atom (provided that R^(2c) is a C₃₋₆ alkyl group having an        alkanoyloxy group and/or a hydroxy group when R^(1c) is a        substituted 1-carboxyethyl group, a substituted carboxy-C₃₋₆        straight-chain alkyl group, a 4-carboxycyclohexylmethyl group or        a 4-carboxymethylphenyl group);    -   (15) The agent as described in the above-mentioned (14), wherein        R^(2c) is a C₃₋₆ alkyl group which may have 1 to 3 substituents        selected from a hydroxy group, acetoxy, propionyloxy,        t-butoxycarbonyloxy and palmitoyloxy;    -   (16) The agent as described in the above-mentioned (14), wherein        R^(3c) is a methyl group;    -   (17) The agent as described in the above-mentioned (14), wherein        W is a chlorine atom;    -   (18) The agent as described in the above-mentioned (14), wherein        the 3-position has an R-configuration and the 5-position has an        S-configuration;    -   (19) The agent as described in the above-mentioned (1) wherein        the compound having inhibitory activity against squalene        synthase is        N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic        acid or        N-[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic        acid;    -   (20) A skeletal muscle protecting agent comprising a compound        having an action of suppressing the decrease of a        geranylgeranylated metabolite in a muscular cell, or a salt        thereof, or a prodrug thereof;    -   (21) A method for protecting skeletal muscle, comprising        administering an effective amount of a compound having        inhibitory activity against squalene synthase, or a salt        thereof, or a prodrug thereof to a mammal;    -   (22) A method for protecting skeletal muscle, comprising        administering an effective amount of a compound having an action        of suppressing the decrease of a geranylgeranylated metabolite        in a muscular cell, or a salt thereof, or a prodrug thereof to a        mammal;    -   (23) Use of a compound having inhibitory activity against        squalene synthase, or a salt thereof, or a prodrug thereof for        manufacturing a skeletal muscle protecting agent;    -   (24) Use of a compound having an action of suppressing the        decrease of a geranylgeranylated metabolite in a muscular cell,        or a salt thereof, or a prodrug thereof for manufacturing a        skeletal muscle protecting agent; and the like. As for the        “compound having inhibitory activity against squalene synthase”        used in the present invention, any compound having inhibitory        activity against squalene synthase may be included, for example,        squalenestatins (e.g., U.S. Pat. Nos. 5,506,262, 5,430,055,        5409950, 5369125, JP-A Nos. 7-173166, 9-124655, 9-227566,        “Annual Review of Microbiology”, Vol. 49, pp. 607-639, 1995,        “Journal of Medicinal Chemistry”, Vol. 38, pp. 3502-3513, 1995,        “Journal of Medicinal Chemistry”, Vol. 39, pp. 207-216, 1996,        “Journal of Medicinal Chemistry”, Vol. 39, pp. 1413-1422, 1996,        etc.), a phosphate compound and a carboxylic acid compound of a        substrate analog (e.g., U.S. Pat. Nos. 5,374,628, 5,441,946,        5,428,028, JP-A No. 7-041554, WO95/04025, “Journal of Medicinal        Chemistry”, Vol. 38, pp. 2596-2605, 1995,        “Arzniemittel-Forschung Drug Research”, Vol. 46, pp. 759-762,        1996, “Journal of Medicinal Chemistry”, Vol. 31, pp. 1869-1871,        1988, “Journal of Medicinal Chemistry”, Vol. 39, pp. 657-660,        1996, “Journal of Medicinal Chemistry”, Vol. 39, pp. 661-664,        1996), carboxylic acid derivatives (e.g., WO97/40006,        WO96/33159, WO95/21834, WO97/48701, EP-A Nos. 645377, 645378,        814080, 790235, JP-A Nos. 7-173120, 10-316634, 10-298134,        10-298177, 10-316617, 9-136880, WO2000/00458, WO2001/98282,        WO98/29380, “Bioorganic Medicinal Chemistry Letters”, Vol. 5,        pp. 1989-1994, 1995, “Bioorganic Medicinal Chemistry Letters”,        Vol. 6, pp. 463-466, 1996, “Journal of Medicinal Chemistry”,        Vol. 40, pp. 2123-2125, 1997, etc.), an amine-based compound        such as quinuclidine derivatives (e.g., U.S. Pat. Nos.        5,385,912, 5,494,918, 5,395,846, 5,451,596, JP-A Nos. 8-134067,        2000-169474, 10-152453, 2000-502716, WO94/03541, WO 94/05660,        WO95/35295, WO96/26938, WO95/31458, WO95/00146, WO97/25043,        WO98/12170, etc.), and Zaragozic acids, particularly, a compound        represented by the formula:        wherein, R₁ is a hydrogen atom or an optionally substituted        hydrocarbon group, R₂ and R₃ are the same or different and a        hydrogen atom, optionally substituted hydrocarbon group or an        optionally substituted heterocyclic group, X′ is a substituent        comprising an optionally esterified carboxyl group, an        optionally substituted carbamoyl group, an optionally        substituted hydroxy group, an optionally substituted amino group        or an optionally substituted heterocyclic residue having a        hydrogen atom which can be deprotonated, Ring A is an optionally        substituted benzene ring or an optionally substituted        heterocyclic ring, Ring J′ is a 7- to 8-membered heterocyclic        ring containing 3 or less hetero atoms, as atoms constituting a        ring, and Ring J′ may further have a substituent in addition to        R₁, R₂, R₃, and X′;        a compound represented by the formula:        wherein, R₁ is a hydrogen atom or an optionally substituted        hydrocarbon group, R₂ and R₃ are the same or different and a        hydrogen atom, optionally substituted hydrocarbon group or        optionally substituted heterocyclic group, X₁ is a bond or        divalent atomic chain, Y is an optionally esterified carboxyl        group, an optionally substituted carbamoyl group, and an        optionally substituted hydroxy group, an optionally substituted        amino group, an optionally substituted heterocyclic residue        having a hydrogen atom which can be deprotonated, Ring B is an        optionally substituted benzene ring; or the like is preferably        used.

Examples of other squalene synthase inhibitors include A-104109 (AbbottLaboratories),

-   F-10863-A (Zaragozic acid D3, Sankyo Co., Ltd.),-   ER-28448, ER-27856 (ER-28448 prodrug) and quinuclidine derivatives    (Eisai),-   RPR-107393 and RPR-101821 (Aventis Pharma Ltd.),-   thiadiazole derivatives (NovoNordisk),-   isopropylamine derivatives (Yamanouchi Pharmaceutical Co., Ltd.),-   isoquinuclidine derivatives (Kotobuki pharmaceutical Co., Ltd.)-   malonic acid derivatives (Nippon Kayaku Co., Ltd.), and-   propionyl derivatives (Daiichi Pharmaceutical Co., Ltd.),    and such squalene synthase inhibitors can be also used in an agent    of the present invention.

The “compound having squalene synthase inhibitory activity” used in thepresent invention can be used in a form of a salt or a prodrug.

As for a “salt” of the compound having squalene synthase inhibitoryactivity used in the present invention, an acid addition salt, which ispharmaceutically and physiologically acceptable, is preferable. For suchsalts, for example, inorganic acids (e.g., hydrochloric acid, phosphoricacid, hydrobromic acid, sulfuric acid, etc.) or organic acids (e.g.,acetic acid, formic acid, propionic acid, fumaric acid, maleic acid,succinic acid, tartaric acid, citric acid, malic acid, oxalic acid,benzoic acid, methanesulfonic acid, benzenesulfonic acid, etc.) or thelike are used. Further, in the case that “compound having squalenesynthase inhibitory activity” used in the present invention has anacidic group such as carboxylic acid or the like, the “compound havingsqualene synthase inhibitory activity” may form salts with, for example,an inorganic base (e.g., an alkali metal or alkaline earth metal such assodium, potassium, calcium, magnesium, or ammonia, etc.) or an organicbase (e.g., tri-C₁₋₃ alkylamine such as triethylamine, etc.).

The “prodrug” of the compound having squalene synthase inhibitoryactivity [hereinafter, referred to as an “SSI Compound”] used in thepresent invention or a salt thereof refers to a compound which isconverted to the SSI Compound by a reaction in vivo under thephysiological condition with an enzyme, a gastric acid or the like, thatis, a compound which is converted to the SSI Compound by enzymaticoxidation, reduction, hydrolysis, etc.; a compound which is converted tothe SSI Compound by hydrolysis or the like with gastric acid, etc.; orthe like. Examples of the prodrug of the SSI Compound include a compoundwherein an amino group of the SSI Compound is substituted with acyl,alkyl or phosphoric acid (e.g., a compound wherein an amino group of theSSI Compound is substituted with eicosanoyl, alanyl,pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl,tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl or tert-butyl,etc.); a compound wherein a hydroxy group of the SSI Compound issubstituted with acyl, alkyl, phosphoric acid or boric acid (e.g., acompound wherein a hydroxy group of the SSI Compound is substituted withacetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl ordimethylaminomethylcarbonyl, etc.); or a compound wherein a carboxylgroup of the SSI Compound is substituted with ester or amide (e.g., acompound wherein a carboxyl group of the SSI Compound is substitutedwith ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethylester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidylester, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,cyclohexyloxycarbonylethyl ester or methyl amide, etc.); and the like.These compounds can be prepared from the SSI Compound by a per se knownmethod.

In addition, the prodrug of the SSI Compound may be a compound which isconverted into the SSI Compound under the physiological conditions asdescribed in “Pharmaceutical Research and Development”, Vol. 7(Molecular Design), pp. 163-198, published in 1990 by HirokawaPublishing Co.

Further, the SSI Compound may be hydrated.

When the optically active form of the SSI Compound is needed, it can beobtained, for example, by using an optically active starting material,or by using a conventional method to optically resolve the racemic formof the SSI Compound. Further, the SSI Compound contains asymmetriccarbon in its molecule, but when the compound has two stereoisomers ofR-configuration and S-configuration, any isomer or a mixture thereof isincluded within the scope of the present invention.

In the formulae (I) and (Ia), examples of the hydrocarbon group in the“optionally substituted hydrocarbon group” represented by R₁ include analiphatic chain (acyclic) hydrocarbon group, an alicyclic hydrocarbongroup and an aryl group, with aliphatic chain hydrocarbon group beingpreferable.

The aliphatic chain hydrocarbon group of the hydrocarbon group includesa linear or branched aliphatic hydrocarbon group such as an alkyl group,an alkenyl group, an alkynyl group. Among these, the branched alkylgroup is preferable. Examples of the alkyl group include C₁₋₇ alkyl suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl and the like, with C₃₋₅ alkylsuch as n-propyl, isopropyl, isobutyl, neopentyl and the like beingpreferable, and isobutyl, neopentyl and the like being particularlypreferable. Examples of the alkenyl group include C₂₋₆ alkenyl such asvinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl,2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like, withvinyl, allyl, isopropenyl, 2-methylallyl, 2-methyl-1-propenyl,2-methyl-2-propenyl, 3-methyl-2-butenyl and the like being particularlypreferable. Examples of the alkynyl group include C₂₋₆ alkynyl such asethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl and the like, with ethynyl, 1-propynyl,2-propynyl being particularly preferable.

The alicyclic hydrocarbon group of the hydrocarbon group includes asaturated or unsaturated alicyclic hydrocarbon group such as acycloalkyl group, a cycloalkenyl group, a cycloalkadienyl group and thelike. As for the cycloalkyl group, a C₃₋₉ cycloalkyl group is preferablewhich includes, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like, with aC₃₋₆ cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl being preferable. Examples of the cycloalkenyl group includea C₅₋₆ cycloalkenyl group such as 2-cyclopenten-1-yl,3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexene-1-yl,1-cyclobuten-1-yl, 1-cyclopenten-1-yl and the like. Examples of thecycloalkadienyl group include a C₅₋₆ cycloalkadienyl group such as2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl.

The aryl group of the hydrocarbon group includes a C₆₋₁₆ monocyclic orfused polycyclic aromatic hydrocarbon group such as phenyl, naphthyl,anthryl, phenanthryl, acenaphthylenyl, with a C₆₋₁₀ aryl group such asphenyl, 1-naphthyl, 2-naphthyl being particularly preferable.

The substituent of the “optionally substituted hydrocarbon group”represented by R₁ includes, an optionally substituted aryl group, anoptionally substituted cycloalkyl group, an optionally substitutedcycloalkenyl group, an optionally substituted heterocyclic group, anoptionally substituted amino group, an optionally substituted hydroxygroup, an optionally substituted thiol group, a halogen atom (e.g.,fluorine, chlorine, bromine, iodine) and oxo etc., and the hydrocarbongroup is optionally substituted with 1 to 5 (preferably 1 to 3)arbitrary substituents at a substitutable position. Examples of the arylgroup of the optionally substituted aryl group include a C₆₋₁₆ arylgroup such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl,with a C₆₋₁₀ aryl group such as phenyl, 1-naphthyl, 2-naphthyl beingpreferable. The substituent of the optionally substituted aryl groupinclude a C₁₋₃ alkoxy group (e.g., methoxy, ethoxy, propoxy, etc.), ahalogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a C₁₋₃alkyl group (e.g., methyl, ethyl, propyl, etc.), and the aryl group isoptionally substituted with 1 to 2 arbitrary substituents. Examples ofthe cycloalkyl group of the optionally substituted cycloalkyl groupinclude a C₃₋₇ cycloalkyl group such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl. The substituent and itssubstituted number of the optionally substituted cycloalkyl group arethe same kind and number as those of the aforementioned substituent ofoptionally substituted aryl group. Examples of the cycloalkenyl group ofthe optionally substituted cycloalkenyl group include a C₃₋₆cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl. The substituent and its substituted number of theoptionally substituted cycloalkenyl group are the same kind and numberas those of the aforementioned substituent of optionally substitutedaryl group. A heterocyclic group of the optionally substitutedheterocyclic group includes an aromatic heterocyclic group and asaturated or unsaturated non-aromatic heterocyclic group (aliphaticheterocyclic group) containing at least one and preferably 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen as an atom constitutingthe ring system (ring atom) with an aromatic heterocyclic group beingpreferable. Examples of the aromatic heterocyclic group include a 5- to6-membered aromatic monocyclic heterocyclic group (e.g., furyl, thienyl,pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, etc.) and an aromatic fusedheterocyclic group in which 2 to 3 of 5- to 6-membered rings are fused(e.g., benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl,isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl,1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthylizinyl, purinyl, pteridinyl,carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl,phenoxathinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.),with the 5- to 6-membered aromatic monocyclic heterocyclic group such asfuryl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl andthe like being preferable. Examples of the non-aromatic heterocyclicgroup include a 4- to 8-membered non-aromatic heterocyclic group such asoxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, piperazinyl. The optionally substituted heterocyclicgroup may contain 1 to 4, preferably 1 to 2 substituents, and thesesubstituents include C₁₋₃ alkyl group (e.g., methyl, ethyl, propyl,etc.) and the like. The substituent in the optionally substituted aminogroup (including amino group, mono- or di-substituted amino group), anoptionally substituted hydroxy group and an optionally substituted thiolgroup include, for example, lower (C₁₋₃) alkyl (e.g., methyl, ethyl,propyl, etc.). Further, when the hydrocarbon group in the optionallysubstituted hydrocarbon group represented by R₁ is an alicylcichydrocarbon group or an aryl group, the substituent may be also a C₁₋₃alkyl group (e.g., methyl, ethyl, propyl, etc.).

In addition, as described above, R₁ may contain an oxo group as asubstituent, and R₁ may contain an acyl carboxylate group which is ahydrocarbon group substituted with oxo. Such examples include C₁₋₆ acylgroup which may contain a substituent (e.g., formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, dimethylacetyl, trimethyl acetyl, etc.). Further, the acyl group may contain 1to 5 substituent at a substitutable position, and the substituentincludes a halogen atom (e.g., fluorine, chlorine, bromine).

In the formulae (I) and (Ia), the “optionally substituted hydrocarbongroup” represented by R₂ and R₃ may include the group descried as the“optionally substituted hydrocarbon group” represented by R₁. However,an alkyl group, an aryl group and substituents thereof may be the groupas follows. That is, as for the alkyl group of the “optionallysubstituted alkyl group” includes a C₁₋₆ lower alkyl group (e.g.,methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.), andpreferably includes a C₁₋₄ alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, tert-butyl. For example, these optionally substitutedalkyl group may contain 1 to 4 substituents, and such substituentsinclude a halogen atom (e.g., fluorine, chlorine, bromine, iodine), C₁₋₄lower alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy,tert-butoxy, etc.) and the like.

The “optionally substituted aryl group” includes monocyclic or fusedpolycyclic aromatic hydrocarbon group such as phenyl, naphthyl, anthryl,phenanthryl, acenaphthylenyl, with phenyl being particularly preferable.The substituent of the “optionally substituted aryl group” includes ahalogen atom (e.g., fluorine, chlorine, bromine, iodine etc.),optionally substituted lower alkyl group, optionally substituted loweralkoxy group, an optionally substituted hydroxy group, nitro and cyano,and may be substituted with 1 to 3 (preferably 1 to 2) of suchsubstituents of the same or different. Examples of the lower alkylinclude a C₁₋₄ alkyl group such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, with methyl and ethyl beingparticularly preferable. Examples of the lower alkoxy include a C₁₋₄alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, with methoxy and ethoxy beingparticularly preferable. The substituent of the optionally substitutedlower alkyl and the optionally substituted lower alkoxy includes ahalogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), and maybe 1 to 5 substituted at an arbitrary position. The substituent in theoptionally substituted hydroxy group includes, for example, a lower(C₁₋₄) alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,tert-butyl etc.), a C₃₋₆ cycloalkyl group (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, etc.), a C₆₋₁₀ aryl group (e.g.,phenyl, 1-naphthyl, 2-naphthyl, etc.), a C₇₋₁₂ aralkyl group (e.g.,benzyl, phenethyl, etc.). Further, these substituents may be takentogether with the adjacent substituents to form a ring; a grouprepresented by

may be used when the aryl group of the “optionally substituted arylgroup” represented by R₂ and R₃ is a phenyl group; and may besubstituted with 1 to 4 substituents such as lower (C₁₋₃) alkyl group(e.g., methyl, ethyl, propyl, isopropyl, etc.).

The heterocyclic group of the “optionally substituted heterocyclicgroup” represented by R₂ and R₃ include a heterocyclic group describedin detail for the “optionally substituted heterocyclic group” given as asubstituent of the “optionally substituted hydrocarbon group”represented by R₁. Among those, 5- to 6-membered aromatic monocyclicheterocyclic ring such as furyl, thienyl, indolyl, isoindolyl,pyrazinyl, pyridyl, pyrimidyl, imidazolyl or the like is particularlypreferable. The substituent of the heterocyclic group includes C₁₋₃alkyl (e.g., methyl, ethyl, propyl, etc.), and said heterocyclic ringmay have 1 to 4 of such substituents.

As described above, as for R₂ and R₃, an optionally substituted phenylgroup is preferable, and more preferably, the substituted phenyl group,especially, a phenyl group substituted with 1 to 3, preferably 1 to 2 ofa halogen atom such as chlorine and bromine, lower (C₁₋₃) alkoxy or thelike is preferable. Further, it is preferable in that any one of R₂ andR₃ is a hydrogen atom.

In the formula (I), the “substituent comprising an optionally esterifiedcarboxyl group” represented by X′ includes an optionally esterifiedcarboxyl group, and a group containing optionally esterified carboxylgroup. The optionally esterified carboxyl group includes the same groupas that defined with respect to Y hereinafter.

The “substituent comprising an optionally substituted carbamoyl group”represented by X′ includes an optionally substituted carbamoyl group,and a group containing an optionally substituted carbamoyl group. Theoptionally substituted carbamoyl group includes the same group as thatdefine with respect to Y hereinafter.

The “substituent comprising an optionally substituted hydroxy group”represented by X′ includes an optionally substituted hydroxy group, anda group containing an optionally substituted hydroxy group. Theoptionally substituted hydroxy group includes the same group as thatdefined with respect to Y hereinafter.

The “substituent comprising an optionally substituted amino group”represented by X′ includes an optionally substituted amino group, and agroup containing an optionally substituted amino group. The optionallysubstituted amino group includes the same group as that defined withrespect to Y hereinafter.

The “substituent comprising an optionally substituted heterocyclicresidue having a hydrogen which can be deprotonated” represented by X′includes an optionally substituted heterocyclic residue having ahydrogen atom which can be deprotonated (i.e., having an active proton),and a group containing an optionally substituted heterocyclic residuehaving a hydrogen atom which can be deprotonated. The optionallysubstituted heterocyclic residue having a hydrogen atom which can bedeprotonated includes the same group as that defined with respect to Yhereinafter.

X′ includes a group represented by the formula (a):

wherein, X is a bond, or divalent or trivalent atomic chain, Y is anoptionally esterified carboxyl group, an optionally substitutedcarbamoyl group, an optionally substituted hydroxy group, an optionallysubstituted amino group, or an optionally substituted heterocyclicresidue having a hydrogen atom which can be deprotonated, and the dottedline is a single or double bond.

In the formula (a), the “divalent atomic chain” represented by X may beany divalent chain having preferably 1 to 7 and more preferably 1 to 4of atoms composing the linear portion, and may contain a side chain.

Example thereof includes a group represented by

wherein, m and n is an integer of 0, 1, 2 or 3, independently, E is abond or an oxygen atom, a sulfur atom, sulfoxide, sulfone, —N(R₅)—,—NHCO—, —CON(R₆)— or —NHCONH—. Herein, R₄ and R₆ represent a hydrogenatom, an optionally substituted lower alkyl group, an optionallysubstituted aralkyl group or an optionally substituted phenyl group. Inaddition, R₅ represents a hydrogen atom, a lower alkyl group, an aralkylgroup or an acyl group.

The alkyl group of the “optionally substituted lower alkyl group”represented by R₄ and R₆ includes a C₁₋₆ linear or branched lower alkylgroup (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, neopentyl, etc.). The optionallysubstituted lower alkyl group may have 1 to 4, preferably 1 to 2substituents, and such substituents include an aromatic heterocyclicgroup (e.g., 5- to 6-membered aromatic heterocyclic ring containing 1 to4 hetero atoms of N, O, S such as furyl, thienyl, indolyl, isoindolyl,pyrazinyl, pyridyl, pyrimidyl, imidazolyl, etc.), an optionallysubstituted amino group, an optionally substituted hydroxy group, anoptionally substituted thiol group, an optionally esterified carboxylgroup and a halogen atom (e.g., fluorine, chlorine, bromine, iodine).The substituent in the optionally substituted amino group (includingamino group, mono- or di-substituted amino group), an optionallysubstituted hydroxy group and an optionally substituted thiol groupinclude, for example, lower (C₁₋₃) alkyl (e.g., methyl, ethyl, propyl,etc.). Examples of the optionally esterified carboxyl group include C₂₋₅alkoxycarbonyl such as methoxycarbonyl ethoxycarbonyl, propoxycarbonyl,phenoxycarbonyl, 1-naphthoxycarbonyl etc. and C₇₋₁₁ aryloxycarbonyl,with methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl being preferable.

The aralkyl group of the “optionally substituted aralkyl group”represented by R₄ and R₆ includes a C₇-C₁₅ aralkyl group such as benzyl,naphthylmethyl, phenylpropyl, phenylbutyl. The optionally substitutedaralkyl group may have 1 to 4, preferably 1 to 2 substituents, and suchsubstituents include a halogen atom (e.g., fluorine, chlorine, bromine,iodine), a C₁₋₃ alkoxy group (e.g., methoxy, ethoxy, propoxy group), ahydroxy group, an amino group, a carboxyl group, a sulfhydryl group.

The substituent of the “optionally substituted phenyl group” representedby R₄ and R₆ includes a halogen atom (e.g., fluorine, chlorine, bromine,iodine), a C₁₋₃ alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), C₁₋₃alkyl (e.g., methyl, ethyl, propyl).

Provided that, R₄ may be different in every methylene chain.

In addition, examples of the “lower alkyl group” and the “aralkyl group”represented by R₅ include a C₁₄ lower alkyl group (e.g., methyl, ethyl,propyl, butyl, tert-butyl, etc.), a C₇₋₁₅ aralkyl group (e.g., benzyl,phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, etc.),respectively.

Examples of the “acyl group” represented by R₅ include a lower (C₁₋₆)alkanoyl group (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), a lower (C₃₋₇) alkenoylgroup (e.g., acryloyl, methacryloyl, crotonoyl, isocrotonoyl, etc.), aC₄₋₇ cycloalkane carbonyl group (e.g., a cyclopropane carbonyl group, acyclobutane carbonyl group, a cyclopentane carbonyl group, a cyclohexanecarbonyl group, etc.), a lower (C₁₋₄) alkane sulfonyl group (e.g.,mesyl, ethane sulfonyl, propane sulfonyl, etc.), a C₇₋₁₄ aroyl group(e.g., benzoyl, p-toluoyl, 1-naphthoyl, 2-naphthoyl, etc.), a C₆₋₁₀ aryllower (C₂₋₄) alkanoyl group (e.g., phenylacetyl, phenylpropionyl,hydroatropoyl, phenylbutyryl, etc.), a C₆₋₁₀ aryl lower (C₃₋₅) alkenoylgroup (e.g., cinnamoyl, atropoyl, etc.), a C₆₋₁₀ arenesulfonyl group(e.g., benzensulfonyl, a p-toluenesulfonyl group, etc.).

Further, X may be a carbon chain having a double bond or -L-CH(OH)— (Lis a bond or a linear or branched alkylene chain). The “carbon chainhaving a double bond” may have 1 to 7 and more preferably 1 to 4 ofcarbon atoms constituting the linear portion, and may also contain aside chain. The double bond in the carbon chain is contained in any oneor both of a linear portion and a branched portion, with preferablycontained in the linear portion. Further, the number of double bondscontained in the carbon chain is not particularly limited, if possible,but 1 to 2 is preferable.

Examples of the carbon chain containing double bond include methine,vinylene, propenylene, butenylene, butadienylene, methylpropenylene,ethylpropenylene, propylpropenylene, methylbutenylene, ethylbutenylene,propylbutenylene, methylbutadienylene, ethylbutadienylene,propylbutadienylene, pentenylene, hexenylene, heptenylene,pentadienylene, hexadienylene, heptadienylene, with methine, vinylene,propenylene, butenylene, butadienylene being preferable. Herein, whenthe carbon chain is trivalent, the carbon chain forms a double bond witha substitutable carbon atom on the ring of ring J′.

Examples of the “linear or branched alkylene chain” represented by Linclude a linear or branched C₁₋₆ alkylene chain, for example, adivalent group such as methylene, ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene, heptamethylene,propylene, ethylmethylene, ethylethylene, propylethylene, butylethylene,methyltetramethylene, methyltrimethylene with a C₁₋₃ chain such asmethylene, ethylene, trimethylene, propylene being preferable.

Among these, X′ is preferably a group represented by the formula (b):—X₁—Ywherein X₁ is a bond or divalent atomic chain, Y is an optionallyesterified carboxyl group, an optionally substituted carbamoyl group, anoptionally substituted hydroxy group, an optionally substituted aminogroup or an optionally substituted heterocyclic group having a hydrogenwhich can be deprotonated.

In the formula (b), the divalent atomic chain represented by X₁ is thedivalent atomic chain as defined as X above in the same manner.

In the formulae (a) and (b), the “divalent atomic chain” represented byX or X₁ may be a linear or branched alkylene chain having 1 to 7 (morepreferably 1 to 4) of carbon atoms constituting the linear portion.Examples of the alkylene chain include a divalent group such asmethylene, ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, heptamethylene, propylene, ethylmethylene, ethylethylene,propylethylene, butylethylene, methyltetramethylene, methyltrimethylene,with a C₁₋₄ chain such as methylene, ethylene, trimethylene, propylenebeing preferable.

In the formulae (a) and (b), the “optionally esterified carboxyl group”represented by Y includes a C₂₋₇ lower alkoxycarbonyl (e.g.,methoxycarbonyl, ethoxycarbonyl, propoxy carbonyl, isopropoxycarbonyl,butoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl,pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, etc.),C₇₋₁₄ aryloxycarbonyl (e.g., phenoxycarbonyl, 1-naphthoxycarbonyl),C₈₋₁₂ aralkyloxycarbonyl (e.g., benzyloxycarbonyl, etc.). Among these, acarboxyl group, methoxycarbonyl, and ethoxycarbonyl are preferable.

The substituent of the “optionally substituted carbamoyl group”represented by Y includes optionally substituted lower (C₁₋₆) alkyl(e.g., methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.),optionally substituted C₃₋₆ cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, etc.), optionally substituted C₆₋₁₄ aryl group(e.g., phenyl, 1-naphthyl, 2-naphthyl, etc.), an optionally substitutedC₇₋₁₁ aralkyl group (e.g., benzyl, phenethyl, etc.), and may besubstituted, the same or different, with 1 to 2 substituents. Thesubstituent in the optionally substituted lower (C₁₋₆) alkyl andoptionally substituted C₃₋₆ cycloalkyl includes carboxyl groupoptionally esterified with lower (C₁₋₅) alkyl (e.g., methyl, ethyl,propyl, isopropyl, butyl, tert-butyl, pentyl, isopentyl, neopentyl), a5- to 6-membered aromatic heterocyclic ring group containing 1 to 4hetero atoms (e.g., furyl, thienyl, indolyl, isoindolyl, pyrazinyl,pyridyl, pyrimidyl, imidazolyl, etc.), an amino group, a hydroxy groupand a phenyl group, and such substituents may be 1 to 3 substituted ofthe same or different substituents. The substituent of the optionallysubstituted aryl group and the optionally substituted aralkyl groupincludes a halogen atom (e.g., fluorine, chlorine, bromine, iodine), andcarboxyl group optionally esterified with a lower (C₁₋₄) alkyl group(e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.). Inaddition, as for the optionally substituted carbamoyl group, the twosubstituents on the nitrogen atoms may be taken together with thenitrogen atoms to form a cyclic amino group, and such cyclic aminogroups include, for example, 1-azetidinyl, 1-pyrrolidinyl, piperidino,morpholino, 1-piperazinyl. Further, the cyclic amino group may alsocontain a substituent.

The substituent of the “optionally substituted hydroxy group”represented by Y includes, for example, lower (C₁₋₄) alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), a C₃₋₆cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc.), an optionally substituted C₆₋₁₀ aryl group (e.g.,phenyl, 1-naphthyl, 2-naphthyl, etc.), an optionally substituted C₇₋₁₁aralkyl group (e.g., benzyl, phenethyl, etc.). The substituent of theoptionally substituted aryl group and the optionally substituted aralkylgroup includes a halogen atom (e.g., fluorine, chlorine, bromine,iodine), carboxyl group optionally esterified with a lower (C₁₋₄) alkylgroup (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.),and the like.

The “optionally substituted amino group” represented by Y includes amono- and di-substituted amino group, and examples of such substituentinclude lower (C₁₋₄) alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, tert-butyl, etc.), a C₃₋₆ cycloalkyl group (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, etc.), an optionally substitutedC₆₋₁₀ aryl group (e.g., phenyl, 1-naphthyl, 2-naphthyl, etc.), and anoptionally substituted C₋₇₋₁₁ aralkyl group (e.g., benzyl, phenethyl,etc.). The substituent of the optionally substituted aryl group and theoptionally substituted aralkyl group includes a halogen atom (e.g.,fluorine, chlorine, bromine, iodine), carboxyl group optionallyesterified with a lower (C₁₋₄) alkyl group (e.g., methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, etc.), and the like, and these groups mayhave 1 to 4 and preferably 1 to 2 substituents. In addition, the twosubstituents on the nitrogen atoms may be taken together with thenitrogen atom to form a cyclic amino group, and such cyclic amino groupsinclude, for example, 1-azetidinyl, 1-pyrrolidinyl, piperidino,morpholino, 1-piperazinyl. Further, the cyclic amino group may alsocontain a substituent.

The heterocyclic residue of the “optionally substituted heterocyclicgroup having a hydrogen atom which can be deprotonated” represented by Yincludes a 5- to 7-membered (preferably 5-membered) monocyclicheterocyclic residue having at least one selected from N, S, O(preferably a nitrogen-containing heterocyclic residue), and may containa hydrogen atom that may form a proton by elimination thereof. Examplesinclude tetrazol-5-yl or a group represented by the formula:

wherein, i is —O— or —S—, j is >C═O, >C═S or >S(O)₂ (among these,2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl,2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl are preferable).

The heterocyclic residue may be protected with an optionally substitutedlower alkyl group (preferably C₁₋₄ alkyl) or an acyl group. Examples ofthe optionally substituted lower alkyl group include C₁₋₄ alkyloptionally substituted with 1) phenyl optionally substituted with C₁₋₃alkyl, nitro or C₁₋₃ alkoxy or 2) C₁₋₃ alkoxy (methyl, triphenylmethyl,methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.).Examples of the acyl group include lower (C₂₋₅) alkanoyl, benzoyl andthe like.

Among these, X′ is preferably an alkyl group substituted with anoptionally esterified carboxyl group, an alkyl group substituted with anoptionally substituted heterocyclic residue having a hydrogen which canbe deprotonated or an alkyl group substituted with an optionallysubstituted carbamoyl group.

In the formula (I), the heterocyclic ring represented by Ring A includesa heterocyclic group described in detail with respect to the substituentof the hydrocarbon group represented by R₁. Among them, a grouprepresented below is preferable.

The substituent of the “optionally substituted benzene ring” and“optionally substituted heterocyclic ring” represented by Ring Aincludes a halogen atom (e.g., fluorine, chlorine, bromine, iodine), anoptionally substituted C₁₋₄ lower alkyl group (e.g., methyl, ethyl,propyl, butyl, tert-butyl, etc.), an optionally substituted C₁₋₄ loweralkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy,tert-butoxy, etc.), a hydroxy group, a nitro group and cyano. Ring A mayhave 1 to 3 and preferably 1 to 2 said substituents. Further, thesesubstituents may be taken together with the adjacent substituents toform a ring. The substituent of the optionally substituted lower alkylgroup and the optionally substituted lower alkoxy group includes ahalogen atom (e.g., fluorine, chlorine, bromine, iodine), in which 1 to3 substituents may be present at an arbitrary position. Ring Asubstituted with methoxy or a chlorine atom is preferable, and Ring Asubstituted with a chlorine atom is particularly preferable.

In the formula (Ia), the substituent of the “optionally substitutedbenzene ring” represented by the Ring B includes a halogen atom (e.g.,fluorine, chlorine, bromine, iodine), an optionally substituted C₁₋₄lower alkyl group (e.g., methyl, ethyl, propyl, butyl, tert-butyl,etc.), an optionally substituted C₁₋₄ lower alkoxy group (e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, etc.), a hydroxygroup, a nitro group and cyano. Ring B may have 1 to 3 and preferably 1to 2 said substituents. Further, these substituents may be takentogether with the adjacent substituents to form a ring. The substituentof the optionally substituted lower alkyl group and the optionallysubstituted lower alkoxy group includes a halogen atom (e.g., fluorine,chlorine, bromine, iodine), in which 1 to 3 substituents may be presentat an arbitrary position. Ring B substituted with methoxy or a chlorineatom is preferable, and Ring B substituted with a chlorine atom isparticularly preferable.

In the formula (I), the heterocyclic ring in the “7- to 8-memberedheterocyclic ring containing 3 or less hetero atoms as atomsconstituting a ring” represented by the ring J′ includes, for example, asaturated or unsaturated 7- to 8-membered heterocyclic ring containingat least one selected from O, S(O)_(q) (q is an integer of 0, 1 or 2)and N. Within the atoms constituting the ring (ring constituting atom)of the heterocyclic ring, there are three or less hetero atoms.

Further, Ring J′, in addition to a group represented by R₁, R₂, R₃ andX′, may have 1 to 2 substituent at a substitutable position. Examples ofthe substituent, when the substituent is attached to a nitrogen atom onRing J′, include an alkyl group (e.g., C₁₋₆ alkyl such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl,neopentyl, etc.), an acyl group (e.g., C₁₋₄ acyl group such as formyl,acetyl, propionyl, butyroyl, etc.). The alkyl group or acyl group mayfurther be substituted with 1 to 5 halogen atom (e.g., fluorine,chlorine, bromine, iodine). Further, when the substituent is attached toa carbon atom on the Ring J′, examples of the substituent include oxo,thioxo, an optionally substituted hydroxy group and an optionallysubstituted amino group. As for the optionally substituted hydroxy groupand the optionally substituted amino group, the “optionally substitutedhydroxy group” and the “optionally substituted amino group” defined as Yabove is mentioned in the same manner.

As for Ring J′, it is preferable to have oxo or thioxo substituted on asubstitutable position, in addition to the group represented by R₁, R₂,R₃ and X′.

Examples of a fused ring with Ring A and the ring J′ include

The formula (I) is preferably a group represented by the formula (I′)

wherein, R₁, R₂, R₃, X′ and Ring A is as defined above. Ring J₁ is a7-membered heterocyclic ring, Z₁ is —N(R₇)— (R₇ is a hydrogen atom, analkyl group or an acyl group), —S(O)_(q) (q is an integer of 0, 1 or 2),—CH₂— or —O—, K is C or N, and G is O or S.

In the formula (I′) above, the alkyl group represented by R₇ includes aC₁₆ linear or branched lower alkyl group (e.g., methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl,neopentyl, etc.), and may be substituted with 1 to 5 halogen atom (e.g.,fluorine, chlorine, bromine, iodine).

Examples of the acyl group represented by R₇ include a C₁₋₄ acyl group(e.g., formyl, acetyl, propionyl, butyroyl, etc.), and which may besubstituted with 1 to 5 halogen atom (e.g., fluorine, chlorine, bromine,iodine).

In the formula (I′), Z₁ is preferably S(O)_(q) (q is an integer of 0, 1or 2) or O. Further, K is preferably C and G is preferably O.

The formula (I′) is more preferably a compound represented by theformula (I″)

wherein, R₁, R₂, R₃, X₁, Y and Ring A is as defined above. Z₂ is S(O) q(q is an integer of 0, 1 or 2) or O.

The compound represented by the formula (I) is preferably the compoundrepresented by the formula (Ia)

The formula (Ia) may be also a compound represented by the formula (Ia′)

wherein, R₁ and Ring B are as defined above. Q is a hydrogen atom or ametal ion, Ring C is an optionally substituted phenyl group. In theformula, the substituents at 3- and 5-position represent trans whichfaces the opposite direction relative to the surface of the 7-memberedring, and (R) represents R-configuration.

In the formula (Ia′), the metal ion represented by Q includes a sodiumion, a potassium ion, a calcium ion, an aluminum ion, with a sodium ionand a potassium ion being preferable.

The substituent of the “optionally substituted phenyl group” representedby Ring C includes the same group as the substituent of the “optionallysubstituted aryl group” described as an example of the “optionallysubstituted hydrocarbon group” defined with respect to R₂ and R₃ above.

Examples of the salt of the compound represented by the formula (I),which are pharmacologically acceptable, include an inorganic salt suchas hydrochloride, hydrobromic acid salt, sulfate, nitrate and phosphate,an organic acid salt such as acetate, tartrate, citrate, fumaric acidsalt, maleate, toluenesulfonate and methanesulfonate, a metal salt suchas a sodium salt, a potassium salt, a calcium salt and an aluminum salt,and a basic salt such as triethylamine salt, guanidine salt, ammoniumsalt, hydrazine salt, quinine salt and cinchonine salt. Among these, asodium salt is preferable.

Specific examples of the compound represented by the formula (I)includes below:

-   (3R,5S)-7-cyano-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2,3-methylenedioxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2,3-ethylenedioxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2,3-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2,4-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2,3-methylenedioxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2,3-ethylenedioxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2,3-methylenedioxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2,3-ethylenedioxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2,3-methylenedioxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2,3-ethylenedioxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2,3-methylenedioxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2,3-ethylenedioxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2,3-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2,4-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2,3-methylenedioxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2,3-ethylenedioxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2,3-methylenedioxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2,3-ethylenedioxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2,3-methylenedioxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2,3-ethylenedioxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic    acid,    (3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-cyano-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic    acid,    (3R)-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-isobutyl-2-oxo-1H-1,4-benzodiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2-chlorophenyl)-2,3,4,5-tetrahydro-1-isobutyl-2-oxo-1H-1,4-benzodiazepine-3-acetic    acid,    N-[[(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-yl]-acetyl]glycin,    (3R,5S)-7-chloro-5-(2-chlorophenyl)-3-dimethylaminocarbonylmethyl-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine,    7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-2,3,4,5-tetrahydro-1H-[1]-benzazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-2-thioxo-4,1-benzoxazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic    acid,    (3R,5S)-7-chloro-1-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-thieno[2,3-e]oxazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(3-hydroxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(4-hydroxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(3-hydroxy-2-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(4-hydroxy-2-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(3-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(3-ethoxy-2-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2-chloro-3-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2-chloro-4-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2-chloro-3-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2-chloro-4-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2-chloro-3-hydroxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2-chloro-4-hydroxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid,    (3R,5S)-7-chloro-5-(2-chloro-3-hydroxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetic    acid,    (3R,5S)-7-chloro-5-(2-chloro-4-hydroxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-acetic    acid; and salts thereof.

The compounds represented by the formula (I) and the salts thereof[hereinafter, sometimes, abbreviated as Compound (I) including salts]are disclosed in, for example, EP-A-567026, WO95/21834 (Japanese PatentApplication No. 6-15531), EP-A-645377 (Japanese Patent Application No.6-229159), EP-A-645378 (Japanese Patent Application No. 6-229160), andit can be prepared based on the disclosure of these publications.

The compound represented by the formula (I) is preferably the compoundrepresented by the formula (Ib):

Preferable examples of the compound represented by the formula (Ib)include:

-   the compound in which R_(b) is a C₁₋₆ alkyl group which may have 1    to 3 substituents selected from a hydroxy group, acetyloxy,    propionyloxy, t-butoxycarbonyloxy, palmitoyloxy,    dimethylaminoacetyloxy and 2-aminopropionyloxy;-   the compound in which R_(b) is a C₃₋₆ branched alkyl group which may    have 1 to 3 substituents selected from a hydroxy group, acetyloxy,    propionyloxy, t-butoxycarbonyloxy, palmitoyloxy,    dimethylaminoacetyloxy and 2-aminopropionyloxy;-   the compound in which R_(b) is 2,2-dimethyl-3-hydroxypropyl,    3-hydroxy-2-hydroxymethyl-2-methylpropyl,    3-acetoxy-2,2-dimethylpropyl,    3-acetoxy-2-hydroxymethyl-2-methylpropyl or    3-acetoxy-2-acetoxymethyl-2-methylpropyl;-   the compound in which R_(1b) is methyl;-   the compound in which W is a chlorine atom;-   the compound in which X_(b) is a group represented by the formula:    wherein, R_(2b) and R_(3b) are each a hydrogen atom, an optionally    substituted hydrocarbon group, an optionally substituted    heterocyclic group or an acyl group, or R_(2b) and R_(3b) may form,    together with the adjacent nitrogen atom, an optionally substituted    5- or 6-membered nitrogen-containing heterocyclic ring optionally    containing 1 to 3 hetero atom selected from a nitrogen atom, a    sulfur atom and an oxygen atom as atoms constituting a ring;-   the compound in which a group represented by X_(b), wherein    -   R_(2b) is a hydrogen atom or a C₁₋₇ alkyl group,    -   R_(3b) is (1) a hydrocarbon group selected from (a) C₁₋₇        alkyl, (b) C₃₋₇ cycloalkyl, (c) C₂₋₆ alkenyl, (d) C₆₋₁₀ aryl        and (e) C₆₋₁₀ aryl-C₁₋₄ alkyl [wherein, (a) C₁₋₇ alkyl, (b) C₃₋₇        cycloalkyl and (c) C₂₋₆ alkenyl may be respectively substituted        with 1 to 4 substituent selected from (i) carboxyl group        optionally esterified with C₁₋₆ alkyl or C₆₋₁₀ aryl-C₁₋₄        alkyl, (ii) phosphate group optionally mono- or di-substituted        with C₁₋₆ alkyl or C₂₋₇ alkanoyloxy-C₁₋₆ alkyl, (iii) a        sulfonate group, (iv) sulfonamide group optionally substituted        with C₁₋₆ alkyl or C₆₋₁₀ aryl-C₁₋₄ alkyl, (v) hydroxy group        optionally alkylated with C₁₋₃ alkyl, (vi) sulfhydryl group        optionally alkylated with C₁₋₃ alkyl, (vii) a carbamoyl        group, (viii) phenyl group optionally substituted with 1 to 5        substituents selected from a hydroxy group, a chlorine atom, a        fluorine atom, aminosulfonyl and amino group optionally mono- or        di-substituted with C₁₋₃ alkyl, (ix) amino group optionally        mono- or di-substituted with C₁₋₃ alkyl, (x) cyclic amino group        derived from piperidine, pyrrolidine, morpholine,        thiomorpholine, piperazine, 4-methylpiperazine,        4-benzylpiperazine, 4-phenylpiperazine,        1,2,3,4-tetrahydroisoquinoline or phthalimide, optionally        substituted with C₁₋₃ alkyl, benzyl or phenyl and (xi) a 5- to        6-membered aromatic heterocyclic group derived from pyridine,        imidazole, indole or tetrazole; and (d) C₆₋₁₀ aryl and (e) C₆₋₁₀        aryl-C₁₋₄ alkyl may be respectively substituted with 1 to 4        substituent selected from (i) carboxyl group optionally        esterified with C₁₋₄ alkyl, (ii) phosphate group optionally        mono- or di-substituted with C₁₋₆ alkyl or C₂₋₇ alkanoyloxy-C₁₋₆        alkyl, (iii) a sulfonate group, (iv) a C₁₋₄ alkylsulfonyl, C₆₋₁₀        arylsulfonyl or C₆₋₁₀ aryl-C₁₋₄ alkylsulfonyl group, (v)        sulfonamide group optionally substituted with C₁₋₆ alkyl or        C₆₋₁₀ aryl-C₁₋₄ alkyl, (vi) C₁₋₃ alkyl group optionally        substituted with carboxyl group optionally esterified with C₁₋₄        alkyl, phosphate group optionally mono- or di-substituted with        C₁₋₆ alkyl, a sulfonate group, C₁₋₄ alkylsulfonyl, C₆₋₁₀        arylsulfonyl or C₆₋₁₀ aryl-C₁₋₄ alkylsulfonyl, sulfonamide group        optionally substituted with C₁₋₆ alkyl or C₆₋₁₀ aryl-C₁₋₄ alkyl        and (vii) a halogen atom],-   (2) tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl,    4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl,    2,3-dihydro-3-oxo-1,2,4-oxadiazolyl,    2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl,    3,5-dioxo-1,2,4-oxadiazolydinyl, 4,5-dihydro-5-oxo-isoxazolyl,    4,5-dihydro-5-thioxo-isoxazolyl,    2,3-dihydro-2-oxo-1,3,4-oxadiazolyl,    2,3-dihydro-3-oxo-1,2,4-tetrazolyl or    2,3-dihydro-3-thioxo-1,2,4-tetrazolyl group, or-   (3) an acyl group selected from (i) a C₂₋₇ alkanoyl group which may    be optionally substituted with 1 to 2 halogen atoms, and (ii) a    C₆₋₁₀ arylsulfonyl group optionally substituted with 1 to 4    substituents selected from C₁₋₃ alkyl, C₁₋₃ alkoxy and a halogen    atom, a C₁₋₄ alkylsulfonyl group or a C₆₋₁₀ aryl-C₁₋₄ alkylsulfonyl    group,-   or R_(2b) and R_(3b) may be taken together with the adjacent    nitrogen atom to form 5- to 6-membered ring derived from piperidine,    piperazine, pyrrolidine, 2-oxopiperazine, 2,6-dioxopiperazine,    morpholine or thiomorpholine [wherein, the 5-membered or 6-membered    ring is optionally substituted with 1 to 4 substituent selected    from (A) hydroxy group optionally substituted with C₁₋₃ alkyl or    C₂₋₇ alkanoyl, (B) carboxyl group optionally esterified with C₁₋₆    alkyl or C₆₋₁₀ aryl-C₁₋₄ alkyl, (C) phosphate group optionally mono-    or di-substituted with C₁₋₆ alkyl or C₂₋₇ alkanoyloxy-C₁₋₆ alky, (D)    a sulfonate group, (E) sulfonamide group optionally substituted with    C₁₋₆ alkyl or C₆₋₁₀ aryl-C₁₋₄ alkyl, (F) C₁₋₆ alkyl and C₂₋₅    alkenyl, each of which is optionally substituted with a carboxyl    group optionally esterified with C₁₋₆ alkyl or C₆₋₁₀ aryl-C₁₋₄    alkyl; a phosphate group optionally mono- or di-substituted with    C₁₋₆ alkyl or C₂₋₇ alkanoyloxy-C₁₋₆ alkyl; a sulfonate group;    sulfonamide group optionally substituted with C₁₋₆ alkyl or C₆₋₁₀    aryl-C₁₋₄ alkyl; a hydroxy group optionally substituted with C₁₋₃    alkyl or C₂₋₇ alkanoyl; a sulfhydryl group optionally alkylated with    C₁₋₃ alkyl; a carbamoyl group; phenyl optionally substituted with 1    to 5 substituents selected from a hydroxy group, a halogen atom, an    aminosulfonyl and an amino group optionally substituted with C₁₋₃    alkyl; an amino group optionally mono- or di-substituted with C₁₃    alkyl; or tetrazolyl, (G) amino group optionally mono- or    di-substituted with C₁₋₃ alkyl, (H) a cyclic amino group derived    from piperidine, pyrrolidine, morpholine, thiomorpholine,    4-methylpiperazine, 4-benzylpiperazine or 4-phenylpiperazine, (I) a    cyano group, (J) a carbamoyl group, (K) an oxo group, (L) a    tetrazolyl or 2,5-dihydro-5-oxo-1,2,4-oxadiazolyl group, (M)    carbamoyl group optionally substituted with C₆₋₁₀ arylsulfonyl, C₁₋₄    alkylsulfonyl or C₆₋₁₀ aryl-C₁₋₄ alkylsulfonyl, (N) sulfhydryl group    optionally alkylated with C₁₋₃ alkyl, and (O) phenyl group which may    be substituted with 1 to 5 substituents selected from a hydroxy    group, a halogen atom, aminosulfonyl and amino group optionally    substituted with C₁₋₃ alkyl];-   the compound wherein in a group represented by X_(b), R_(2b) and    R_(3b) may be taken together with the adjacent nitrogen atom of a    carbamoyl group to form a 5- or 6-membered ring derived from    piperidine, piperazine, pyrrolidine, 2-oxopiperazine or    2,6-dioxopiperazine, and the 5- or 6-membered ring is optionally    substituted with C₁₋₆ alkyl group which may have 1 to 2 substituents    selected from (i) carboxyl group optionally esterified with C₁₋₆    alkyl or C₆₋₁₀ aryl-C₁₋₄ alkyl, (ii) phosphate group optionally    mono- or di-substituted with C₁₋₆ alkyl or C₂₋₇ alkanoyl-C₁₋₆    alkyl, (iii) a sulfonate group, (iv) sulfonamide group optionally    substituted with C₁₋₆ alkyl or C₆₋₁₀ aryl-C₁₋₄ alkyl, (v) hydroxy    group optionally alkylated with C₁₋₃, (vi) sulfhydryl group    optionally alkylated with C₁₋₃ alkyl, (vii) a carbamoyl    group, (viii) phenyl group which may be substituted with 1 to 5    substituents selected from a hydroxy group, a halogen atom,    aminosulfonyl and amino optionally substituted with C₁₋₃ alkyl, (ix)    amino group optionally mono- or di-substituted with C₁₋₃ alkyl,    and (x) a tetrazolyl group;-   the compound wherein in a group represented by X_(b), R_(2b) is a    hydrogen atom or C₁₋₇ alkyl and R_(3b) is C₁₋₄ alkylsulfonyl;-   the compound in which a heterocyclic group represented by X_(b) is    tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl,    4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl,    2,3-dihydro-3-oxo-1,2,4-oxadiazolyl,    2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl,    3,5-dioxo-1,2,4-oxadiazolydinyl, 4,5-dihydro-5-oxo-isoxazolyl,    4,5-dihydro-5-thioxo-isoxazolyl,    2,3-dihydro-2-oxo-1,3,4-oxadiazolyl,    2,3-dihydro-3-oxo-1,2,4-tetrazolyl or    2,3-dihydro-3-thioxo-1,2,4-tetrazolyl;-   the compound in which R_(1b) is methyl, W is a chlorine atom, R_(b)    is C₃₋₆ branched alkyl which is substituted with 1 to 3 substituents    selected from a hydroxy group, acetyloxy, propionyloxy,    tert-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and    2-aminopropionyloxy, and X_(b) is a group represented by the    formula:    wherein, R_(2b′) is a hydrogen atom or C₁₋₇ alkyl and R_(3b′) is    C₁₋₄ alkyl;-   the compound in which R_(1b) is methyl, W is a chlorine atom, R_(b)    is C₃₋₆ branched alkyl which is substituted with 1 to 3 substituents    selected from a hydroxy group, acetyloxy, propionyloxy,    tert-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and    2-aminopropionyloxy, and X_(b) is a group represented by the    formula:    wherein, R_(b′) is a hydrogen atom or C₁₋₇ alkyl, and n is an    integer of 1 to 5;-   the compound in which R_(1b) is methyl, W is a chlorine atom, R_(b)    is C₃₋₆ branched alkyl which is substituted with 1 to 3 substituents    selected from a hydroxy group, acetyloxy, propionyloxy,    tert-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and    2-aminopropionyloxy, and X_(b) is a group represented by the    formula:    wherein, R″ is a hydrogen atom or C₁₋₄ alkyl;-   the compound in which R_(1b) is methyl, W is a chlorine atom, R_(b)    is C₃₋₆ branched alkyl which is substituted with 1 to 3 substituents    selected from a hydroxy group, acetyloxy, propionyloxy,    tert-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and    2-aminopropionyloxy, and X_(b) is tetrazolyl;-   the compound in which R_(b) is lower alkyl optionally substituted    with 1 or 2 hydroxy groups, and X_(b) is (1) carbamoyl group    optionally substituted with a hydrocarbon group selected from (a)    C₁₋₇ alkyl, (b) C₃₋₇ cycloalkyl, (c) C₂₋₆ alkenyl, (d) C₆₋₁₀ aryl    and (e) C₇₋₁₄ arylalkyl [wherein, (a) C₁₋₇ alkyl, (b) C₃₋₇    cycloalkyl, and (c) C₂₋₆ alkenyl may be respectively substituted    with 1 to 4 substituent selected from (i) carboxyl group optionally    esterified with C₁₋₆ alkyl or C₇₋₁₀ arylalkyl, (ii) a phosphate    group, (iii) a sulfonate group, (iv) sulfonamide group optionally    substituted with C₁₋₆ alkyl or C₇₋₁₀ arylalkyl, (v) hydroxy group    optionally alkylated with C₁₋₃ alkyl, (vi) sulfhydryl group    optionally alkylated with C₁₋₃ alkyl, (vii) a carbamoyl    group, (viii) an phenyl group optionally substituted with    substituents selected from a hydroxy group, a chlorine atom, a    fluorine atom, aminosulfonyl and amino group optionally mono- or    di-substituted with C₁₋₃ alkyl, (ix) amino group optionally mono- or    di-substituted with C₁₋₃ alkyl, and (x) cyclic amino group derived    from piperidine, pyrrolidine, morpholine, thiomorpholine,    piperazine, 4-methylpiperazine, 4-benzylpiperazine, or    4-phenylpiperazine, which may be substituted with C₁₋₃ alkyl, benzyl    or phenyl and (xi) 5- or 6-memebered aromatic heterocyclic group    derived from pyridine, imidazole, indole or tetrazole, and (d) C₆₋₁₀    aryl and (e) C₇₋₁₄ arylalkyl may be respectively substituted with 1    to 4 substituent selected from (i) carboxyl group optionally    esterified with C₁₋₄ alkyl, (ii) a phosphate group, (iii) a    sulfonate group, (iv) sulfonamide group optionally substituted with    C₁₋₆ alkyl or C₇₋₁₀ arylalkyl, (v) C₁₋₃ alkyl group optionally    substituted with carboxyl group optionally esterified with C₁₋₄    alkyl, a phosphate group, a sulfonate group, or sulfonamide group    optionally substituted with C₁₋₆ alkyl or C₇₋₁₀ arylalkyl, and (iv)    a halogen atom],-   (2) tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl,    4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl,    2,3-dihydro-3-oxo-1,2,4-oxadiazolyl,    2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl,    3,5-dioxo-1,2,4-oxadiazolydinyl, 4,5-dihydro-5-oxo-isoxazolyl,    4,5-dihydro-5-thioxo-isoxazolyl,    2,3-dihydro-2-oxo-1,3,4-oxadiazolyl,    2,3-dihydro-3-oxo-1,2,4-tetrazolyl or    2,3-dihydro-3-thioxo-1,2,4-tetrazolyl group,-   (3) carbamoyl group optionally substituted with an acyl group    selected from (i) a C₂₋₇ alkanoyl group which is optionally    substituted with 1 to 2 halogen atoms, and (ii) a C₆₋₁₀ arylsulfonyl    group, a C₁₋₄ alkylsulfonyl group or a C₇₋₁₄ arylalkylsulfonyl    group, each of which may be optionally substituted with 1 to 4    substituents selected from C₁₋₃ alkyl, C₁₋₃ alkoxy and a halogen    atom, or-   (4) a cyclic amino carbonyl group derived from piperidine,    piperazine, pyrrolidine, 2-oxopiperazine, 2,6-dioxopiperazine,    morpholine and thiomorpholine [wherein, the cyclic amino carbonyl    group is optionally substituted with 1 to 4 substituent selected    from (A) a hydroxy group, (B) carboxyl group optionally esterified    with C₁₋₄ alkyl, (C) a phosphate group, (D) a sulfonate group, (E)    sulfonamide group optionally substituted with C₁₋₆ alkyl or C₇₋₁₀    arylalkyl, (F) C₁₋₃ alkyl or C₂₋₅ alkenyl, each of which may be    substituted with the above-mentioned (A), (B), (C), (D) or (E), (G)    amino group optionally mono- or di-substituted with C₁₋₃ alkyl, (H)    a cyclic amino group derived from piperidine, pyrrolidine,    morpholine, thiomorpholine, 4-methylpiperazine, 4-benzylpiperazine    or 4-phenylpiperazine, (I) a cyano group, (J) a carbamoyl group, (K)    oxo, (L) C₁₋₃ alkoxy, (M) a heterocyclic group derived from    tetrazolyl or 2,5-dihydro-5-oxo-1,2,4-oxadiazolyl, and (N) carbamoyl    group optionally substituted with C₆₋₁₀ arylsulfonyl, C₁₋₄    alkylsulfonyl or C₇₋₁₄ arylalkylsulfonyl];-   the compound in which R_(b) is a 2,2-dimethyl-3-hydroxypropyl group;    or the like.

In the aforementioned formula, the lower alkyl group represented byR_(b) includes, for example, C₁₋₆ alkyl such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl and hexyl.Among these, a C₃₋₆ alkyl group is preferable, and a C₄₋₅ alkyl group ismore preferable. In particular, a C₄₋₅ branched alkyl group such asisobutyl, neopentyl or the like, is preferable.

The substituent of the lower alkyl represented by R_(b) includes, forexample, hydroxy group optionally substituted with C₂₋₂₀ alkanoyl orC₁₋₇ alkyl or the like. Examples of these substituents include a hydroxygroup, acetyloxy, propionyloxy, tert-butoxycarbonyloxy, palmitoyloxy,dimethylaminoacetyloxy and 2-aminopropionyloxy.

One to three of these substituents may be present at their substitutablepositions.

In addition, examples of the optionally substituted lower alkylrepresented by R_(b) include 2,2-dimethyl-3-hydroxypropyl,3-hydroxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2,2-dimethylpropyl,3-acetoxy-2-hydroxymethyl-2-methyl-propyl and3-acetoxy-2-acetoxymethyl-2-methylpropyl.

The optionally substituted carbamoyl group represented by X_(b) includesthe group represented by the formula:

Examples of the “optionally substituted hydrocarbon group” representedby R_(2b) and R_(3b) include an optionally substituted C₁₇ linear orbranched alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, 1,1-dimethylethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl,1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, neopentyl, hexyl, heptyl),an optionally substituted C₃₋₇ cycloalkyl group (cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, etc.), anoptionally substituted C₂₋₆ linear or branched alkenyl group (e.g.,vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl,2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc.), anoptionally substituted C₆₋₁₀ aryl group (e.g., phenyl and naphthylgroup) and an optionally substituted C₇₋₁₄ arylalkyl group (e.g.,benzyl, phenethyl and naphthylmethyl).

The substituent of the “optionally substituted C₁₋₇ linear or branchedalkyl group, optionally substituted C₃₋₇ cycloalkyl group and optionallysubstituted C₂₋₆ linear or branched alkenyl group” includes, forexample, carboxyl group optionally esterified with C₁₋₆ alkyl group orC₆₋₁₀ aryl-C₁₋₄ alkyl group (e.g., methyl, ethyl, propyl, isopropyl,butyl, tert-butyl, phenyl, benzyl, etc.), phosphate group optionallymono- or di-substituted with C₁₋₆ alkyl group (e.g., methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl,hexyl, etc.) or C₂₋₇ alkanoyloxy-C₁₋₆ alkyl such as acetyloxymethyl orpivaloyloxymethyl group, a sulfonate group, sulfonamide group optionallysubstituted which is substituted with C₁₋₆ alkyl group or C₆₋₁₀aryl-C₁₋₄ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, phenyl, benzyl, etc.), hydroxy group and sulfhydryl group,each optionally alkylated with C₁₋₃ alkyl group (e.g., methyl, ethyl,propyl, etc.), a carbamoyl group, phenyl group optionally substitutedwith 1 to 5 substituents [e.g., a hydroxy group, chlorine, fluorine, anaminosulfonyl group or amino group optionally substituted with C₁₋₃alkyl group (e.g., methyl, ethyl, propyl, etc.)], an amino groupoptionally mono- or di-substituted with C₁₋₃ alkyl group (e.g., methyl,ethyl, propyl, etc.), a cyclic amino group (e.g., 5- or 6-memberedcyclic amino group derived from cyclic amine such as piperidine,pyrrolidine, morpholine, thiomorpholine, piperazine, 4-methylpiperazine,4-benzylpiperazine, 4-phenylpiperazine, 1,2,3,4-tetrahydroisoquinoline,phthalimide, or the like, which may be optionally substituted with aC₁₋₃ alkyl group, benzyl, phenyl or the like, and optionally contains anoxygen atom or a sulfur atom as additional atoms constituting a ring)and 5- to 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, S (e.g. pyridine, imidazole, indole,tetrazole, etc).

In addition, as for the substituent of C₆₋₁₀ aryl group and C₆₋₁₀aryl-C₁₋₄ alkyl group as the substituent of an optionally substitutedamino group which forms a carbamoyl group of the “optionally substitutedcarbamoyl group” represented by X_(b) includes an optionally esterifiedcarboxyl group with C₁₋₄ alkyl group (methyl, ethyl, propyl, tert-butylgroup, etc.), phosphate group optionally mono- or di-substituted withC₁₋₆ alkyl group (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,n-pentyl, isopentyl, neopentyl, hexyl) or C₂₋₇ alkanoyloxy-C₁₋₆ alkylsuch as pivaloyloxymethyl group or acetyloxymethyl group, a sulfonategroup, C₁₋₄ alkylsulfonyl, C₆₋₁₀ arylsulfonyl or C₆₋₁₀ aryl-C₁₋₄alkylsulfonyl, sulfonamide group optionally substituted with a C₁₋₆alkyl group or a C₆₋₁₀ aryl-C₁₋₄ alkyl group (e.g., methyl, ethyl,propyl, isopropyl, butyl, tert-butyl, benzyl, etc.) and an optionallyesterified carboxyl group with a C₁₋₄ alkyl group, phosphate groupoptionally mono- or di-substituted with a C₁₋₆ alkyl group such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl,isopentyl, neopentyl, hexyl, or the like or C₂₋₇ alkanoyloxy-C₁₋₆ alkylsuch as a pivaloyloxymethyl group, C₁₋₃ alkyl group (e.g., methyl,ethyl, propyl and isopropyl) optionally substituted with a sulfonategroup and sulfonamide group optionally substituted with C₁₋₆ alkyl or aC₆₋₁₀ aryl-C₁₋₄ alkyl group, and a halogen atom (fluorine and chlorine),and the like.

The “hydrocarbon group” may have 1 to 5 substituents at a substitutableposition.

The “optionally substituted heterocyclic group” represented by R_(2b)and R_(3b) may have 1 to 2 substituent preferably such as an oxo groupor a thioxo group, and may be preferably a heterocyclic group having ahydrogen which can be deprotonated. These heterocyclic groups ispreferably a 5- to 6-membered heterocyclic group containing 1 to 4,preferably 2 to 3 hetero atoms selected from S, O or N. Specificexamples include tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl,4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl,2,3-dihydro-3-oxo-1,2,4-oxadiazolyl,2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl, 3,5-dioxo-1,2,4-oxadiazolydinyl,4,5-dihydro-5-oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl,2,3-dihydro-2-oxo-1,3,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-tetrazolyland 2,3-dihydro-3-thioxo-1,2,4-tetrazolyl. Among these, tetrazolyl groupis preferable.

Examples of the “acyl group” represented by R_(2b) and R_(3b) include anacyl carboxylate group derived from carboxylate (e.g., C₂₋₇ acylcarboxylate group such as acetyl, propionyl, butyryl, benzoyl, etc.) andC₆₋₁₀ arylsulfonyl group, a C₁₋₄ alkylsulfonyl group and C₆₋₁₀ aryl-C₁₋₄alkylsulfonyl group which may optionally have a substituent (e.g.,methylsulfonyl, ethylsulfonyl, phenylsulfonyl, naphthylsulfonyl,phenylmethylsulfonyl, phenylethylsulfonyl, naphthylmethylsulfonyl,naphthylethylsulfonyl, etc.). The substituents of aryl, alkyl andarylalkylsulfonyl group include C₁ to C₃ alkyl (e.g., methyl, ethyl,propyl, etc.), C₁₋₃ alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), ahalogen atom (e.g., chlorine, fluorine, bromine), and 1 to 4, preferably1 to 2, thereof may be present at a substitutable position.

The aforementioned acyl carboxylate group may have 1 to 2 halogen atoms(chlorine, fluorine, bromine) as a substituent.

Examples of the cyclic amino group optionally substituted with C₁₋₃alkyl, C₂₋₇ alkanoyl or the like, which is formed by taking togetherR_(2b) and R_(3b) with the adjacent nitrogen atom of carbamoyl group,include a group derived from 5- to 6-membered cyclic amine such ascyclic amine (e.g. piperazine, piperidine, pyrrolidine, piperazin-2-one,piperazine-2,6-dione, morpholine, thiomorpholine, etc) which mayadditionally contain 1 to 3 hetero atoms selected from a nitrogen atom,a sulfur atom, or an oxygen atom as atoms constituting a ring. Suchcyclic amino group may have 1 to 4, preferably 1 to 2 substituents.Examples of the substituents include hydroxy group optionallysubstituted with C₁₋₃ alkyl group or C₂₋₇ alkanoyl, carboxyl groupoptionally esterified with C₁₋₄ alkyl group (methyl, ethyl, propyl,tert-butyl, etc.) and C₇₋₁₀ arylalkyl, phosphate group optionally mono-or di-substituted with C₁₋₆ alkyl or C₂₋₇ alkanoyloxy-C₁₋₆ alkyl group(acetyloxymethyl group, pivaloyloxymethyl group), a sulfonate group, andsulfonamide group optionally substituted with C₁₋₆ alkyl or C₆₋₁₀aryl-C₁₋₄ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, benzyl, etc.), C₁₋₆ alkyl and C₂₋₅ alkenyl, each optionallysubstituted with “carboxyl group optionally esterified with C₁₋₆ alkylor C₆₋₁₀ aryl-C₁₋₄ alkyl, phosphate group optionally mono- ordi-substituted with C₁₋₆ alkyl or C₂₋₇ alkanoyloxy-C₁₋₆ alkyl group(acetyloxymethyl group, pivaloyloxymethyl group, etc.), a sulfonategroup, sulfonamide group optionally substituted with C₁₋₆ alkyl or C₆₋₁₀aryl-C₁₋₄ alkyl group, hydroxy group optionally substituted with C₁₋₃alkyl or C₂₋₇ alkanoyl, sulfhydryl group optionally alkylated with C₁₋₃alkyl, a carbamoyl group, phenyl group optionally substituted with 1 to5 substituents (e.g., a hydroxy group, a halogen atom, aminosulfonyl,amino group optionally substituted with C₁₋₃ alkyl, etc.), amino groupoptionally mono- or di-substituted with C₁₋₃ alkyl or tetrazolyl group”,amino group optionally mono- or di-substituted with C₁₋₃ alkyl (e.g.,methyl, ethyl, propyl, etc.), a cyclic amino group (a group derived from5- to 6-membered cyclic amine which may contain additional hetero atomsas atoms constituting a ring selected from a nitrogen atom, a sulfuratom, or an oxygen and which may be substituted with C₁-C₃ alkyl,benzyl, phenyl, or the like, for example, piperidine, pyrrolidine,morpholine, thiomorpholine, 4-methylpiperazine, 4-benzylpiperazine,4-phenylpiperazine, or the like), a cyano group, a carbamoyl group, anoxo group, C₁₋₃ alkoxy (e.g., methoxy, ethoxy, ethylenedioxy, etc.),heterocyclic group optionally substituted with an oxo group or thioxogroup having a hydrogen which can be deprotonated as mentioned above(e.g. tetrazolyl, 2,5-dihydro-5-oxo-1,2,4-oxadiazolyl, etc.), C₆₋₁₀arylsulfonyl, C₆₋₁₀ aryl-C₁₋₄ alkylsulfonyl and C₁₋₄ alkylsulfonyl(methylsulfonyl, ethylsulfonyl, propyl sulfonyl, butylsulfonyl,isopropyl sulfonyl, tert-butylsulfonyl, phenyl, sulfonyl,benzylsulfonyl, etc.) as exemplified for the substituent of anoptionally substituted amino group which forms carbamoyl of the“optionally substituted carbamoyl group” represented by X, sulfhydrylgroup optionally alkylated with C₁₋₃ alkyl, or carbamoyl groupsubstituted with phenyl optionally substituted with 1 to 5 substituents(e.g. a hydroxy group, a halogen atom, an aminosulfonyl and amino groupoptionally substituted with C₁₋₃ alkyl).

Examples of the carbamoyl group, which may have substituents representedby X_(b) include:

R_(2b′), and R_(b′) include a hydrogen atom and C₁₋₇ alkyl. The hydrogenatom is particularly preferable.

The C₁₋₇ alkyl represented by R_(2b), R_(2b′) and R_(b′) includes thosesuch as the aforementioned C₁₋₇ alkyl of the “hydrocarbon group”.

R″ includes a hydrogen atom and C₁₋₄ alkyl. The hydrogen atom isparticularly preferable.

C₁₋₄ alkyl represented by R_(3b′), and R″ includes, for example, methyl,ethyl, propyl, isopropyl, n-butyl, tert-butyl.

As for the optionally substituted heterocyclic group having a hydrogenwhich can be deprotonated represented by X_(b), a nitrogen-containing(preferably including 1 to 4 nitrogen atoms) 5- to 6-memberedheterocyclic ring having active proton of Broensted acid is preferable,and those containing 1 to 4, preferably 2 to 3 of a nitrogen atom, asulfur atom, an oxygen atom may be preferable. These substituentsinclude, an oxo group and a thioxo group, and 1 to 2 (preferably 1) ofsuch substituents may be present. The “optionally substitutedheterocyclic group having a hydrogen which can be deprotonated”represented by X includes, for example, a group as exemplified as the“optionally substituted heterocyclic group” as the substituent of the“optionally substituted carbamoyl group” represented by X such astetrazolyl, 2,5-dihydro-5-oxo-1,2,4-oxadiazolyl and the like.

Examples of the “lower alkyl group” represented by R_(1b) include aC₁-C₆ alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl,tert-butyl, pentyl, hexyl and the like. Among these, C₁-C₃ alkyl groupis preferable. In the view of pharmacological activity, a methyl groupis particularly preferable as R_(1b).

Examples of the “halogen atom” represented by W include chlorine,fluorine, bromine, iodine atoms. The chlorine atom is particularlypreferable.

Examples of the salts of the compound represented by the formula (Ib),include pharmacologically acceptable salts, for example, inorganic saltssuch as hydrochloride, hydrobromate, sulfate, nitrate, phosphate and thelike; organic salts such as acetate, tartrate, citrate, fumarate,maleate, toluenesulfonate, methanesulfonate and the like; metal saltssuch as a sodium salt, a potassium salt, a calcium salt, an aluminumsalt and the like; and basic salts such as a triethylamine salt, aguanidine salt, an ammonium salt, a hydrazine salt, a quinine salt, acinchonine salt and the like.

In addition, hydrates as well as non-hydrates of the compoundrepresented by the formula (Ib) are included within the scope of thepresent invention.

The compound represented by the formula (Ib) and salts thereof containsasymmetric carbon atoms at 3- and 5-positions, herein the trans isomerwherein the substituents on 3- and 5-positions are directed in theopposite direction relative to the surface of a 7-membered ring ispreferable, and the isomer wherein the absolute configuration at3-position is R-configuration, and the absolute configuration at5-position is S-configuration is particularly preferable.

Among the compounds represented by the formula (Ib) and salts thereof,the following concrete compounds are preferable.

N-methanesulfonyl-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetamide,N-methanesulfonyl-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetamide,N-[2-(pyrrolidin-1-yl)ethyl]-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetamide,N-[2-(pyrrolidin-1-yl)ethyl]-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetamide,N-methanesulfonyl-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetamide,N-methanesulfonyl-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetamide,N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidin-4-aceticacid,N-[[(3R,5S)-1-(3-hydroxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidin-4-aceticacid,N-[[(3R,5S)-1-(2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidin-4-aceticacid,N-[[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidin-4-aceticacid, ethylN-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetate,ethylN-[[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetate,(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl-4,1-benzoxapin-2-one,(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl-4,1-benzoxazepin-2-one,(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl-4,1-benzoxazepin-2-one,(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl-4,1-benzoxazepin-2-one,N-[2-(pyrrolidin-1-yl)ethyl]-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetamide,and the like.

The compound represented by the formula (Ib) and salts thereof can beprepared by the methods disclosed in the publications, for example,EP-A-567026, WO95/21834 (PCT application based on Japanese PatentApplication No. 6-15531), EP-A-645377 (an application based on JapanesePatent Application No. 6-229159), EP-A-645378 (an application based onJapanese Patent Application No. 6-229160), WO97/10224 and the like, orthe methods similar thereto.

The compound represented by the formula (Ic) is preferable as a compoundrepresented by the formula (I).

Preferable examples of the compound represented by the formula (Ic)include:

-   the compound in which R^(1c) is a 3-carboxypropyl group, a    1-carboxyethyl group, or a C₃₋₆ linear alkyl-sulfonyl group, a    (carboxy-C₅₋₇ cycloalkyl)-C₁₋₃ alkyl group, a (carboxyfuryl)-alkyl    group, a carboxy-C₆₋₁₀ aryl group, a (carboxy-C₂₋₃ alkyl)-C₆₋₁₀ aryl    group or a (carboxy-C₁₋₃ alkyl)-C₇₋₁₄ aralkyl group, each of which    may be optionally substituted;-   the compound in which R^(1c) is a (carboxy-C₁₋₄ alkyl)-C₆₋₁₀ aryl    group which maybe optionally substituted;-   the compound in which R^(1c) is a (carboxy-C₂₋₃ alkyl)-C₆₋₁₀ aryl    group which may be optionally substituted;-   the compound in which R^(1c) is a (carboxy-C₂₋₃ alkyl)-phenyl group    which may be optionally substituted;-   the compound in which R^(1c) is a (carboxyfuryl)-alkyl group which    may be optionally substituted;-   the compound in which R^(2c) is a C₃₋₆ alkyl group which have    alkanoyloxy group and/or a hydroxy group;-   the compound in which R^(2c) is a C₃₋₆ alkyl group which may have 1    to 3 substituents selected from a hydroxy group, acetoxy,    propionyloxy, tert-butoxycarbonyloxy or palmitoyloxy;-   the compound in which R^(2c) is 2,2-dimethylpropyl,    3-hydroxy-2,2-dimethylpropyl or 3-acetoxy-2,2-dimethylpropyl;-   the compound in which R^(3c) is a methyl group;-   the compound in which W is a chlorine atom;-   the compound having R-configuration at 3-position, and    S-configuration at 5-position.

In the aforementioned the formula, R^(1c) represents an optionallysubstituted 1-carboxyethyl group, an optionally substituted carboxy-C₃₋₆linear alkyl group, an optionally substituted C₃₋₆ linear alkyl-sulfonylgroup, an optionally substituted (carboxy-C₅₋₇ cycloalkyl)-C₁₋₃ alkylgroup, or formula —X^(1c)—X^(2c)—Ar—X^(3c)—X^(4c)—COOH (wherein X^(1c)and X^(4c) respectively represents a bond or a C₁₋₄ alkylene group whichmay have substituents, X^(2c) and X^(3c) respectively represents a bond,—O— or —S— and Ar is an optionally substituted divalent aromaticheterocyclic group. However, when X^(1c) is a bond, X^(2c) represents abond, and when X^(4c) is a bond, X^(3c) represents a bond).

Examples of the C₃₋₆ linear alkyl group in the optionally substitutedcarboxy-C₃₋₆ linear alkyl group represented by R^(1c) include n-propyl,n-butyl, n-pentyl, n-hexyl. Among these, n-propyl and n-butyl arepreferable, and n-propyl is more preferable.

Examples of the C₃₋₆ linear alkyl group in the optionally substitutedC₃₋₆ linear alkyl-sulfonyl group represented by R^(1c) include n-propyl,n-butyl, n-pentyl, n-hexyl. Among these, n-propyl and n-butyl arepreferable, and n-propyl is more preferable.

Examples of the C₅₋₇ cycloalkyl group in the optionally substituted(carboxy-C₅₋₇ cycloalkyl)-C₁₋₃ alkyl group represented by R^(1c) includecyclopentyl, cyclohexyl and cycloheptyl. Among these, cyclopentyl andcyclohexyl are preferable, and cyclohexyl is more preferable.

Examples of the C₁₋₃ alkyl group in the optionally substituted(carboxy-C₅₋₇ cycloalkyl)-C₁₋₃ alkyl group represented by R^(1c) includemethyl, ethyl, n-propyl and isopropyl. Among these, methyl and ethyl arepreferable, and methyl is more preferable.

In the group represented by formula —X^(1c)—X^(2c)—Ar—X^(3c)—X^(4c)—COOHin R^(1c), examples of the “C₁₋₄ alkylene group” in the “optionallysubstituted C₁₋₄ alkylene group” represented by X^(1c) and X^(4c)include methylene, dimethylene, trimethylene, tetramethylene, andpreferably C₁₋₃ alkylene group, and among them the linear one may bepreferably used.

Examples of the “divalent aromatic ring group” in the “optionallysubstituted divalent aromatic ring group” represented by Ar include adivalent aromatic hydrocarbon group or a divalent aromatic heterocyclicgroup.

Herein, examples of the divalent aromatic hydrocarbon group include agroup formed by removing one hydrogen atom from C₆₋₁₀ aryl group (e.g.,phenyl, naphthyl, etc.), and phenylene is preferably used as a divalentaromatic hydrocarbon group.

Examples of divalent aromatic heterocyclic group include a group formedby removing one hydrogen atom from the aromatic heterocyclic group,which contains at least 1 (preferably 1 to 4, more preferably 1 to 2) of1 to 3 (preferably 1 to 2) hetero atoms selected from an oxygen atom, asulfur atom and a nitrogen atom as an atom constituting a ring-system(annular atom).

Herein, examples of the aromatic heterocyclic group include a 5- to6-membered aromatic monocyclic heterocyclic group such as furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl (preferably,furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyridyl, etc.) and an8- to 12-membered aromatic fused heterocyclic group such asbenzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl,1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl,benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl,quinolyl, isoquinolyl, cinnolyl, quinazolinyl, quinoxalinyl,phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl,α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl,phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl,phenathridinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo [1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl(preferably, a heterocyclic group in which the aforementioned 5- to6-membered aromatic monocyclic heterocyclic group is fused with abenzene ring, or a heterocyclic group in which two heterocyclic groups,the same or different, selected from the aforementioned 5- to 6-memberedaromatic monocyclic heterocyclic group are fused, and more preferably, aheterocyclic group in which the aforementioned 5- to 6-aromaticmonocyclic heterocyclic group is fused with a benzene ring).

The substituent of “C₁₋₄ alkylene group” in the “optionally substitutedC₁₋₄ alkylene group” represented by X^(1c) and X^(4c); and thesubstituent of “divalent aromatic ring group” in the “optionallysubstituted divalent aromatic ring group” include: (i) carboxyl groupoptionally esterified with a C₁₋₆ alkyl group or a C₆₋₁₀ aryl-C₁₋₄ alkylgroup (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,phenyl, benzyl, etc.); (ii) phosphate group optionally mono- ordi-substituted with C₁₋₆ alkyl (e.g., methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, hexyl,etc.) or C₂₋₇ alkanoyloxy-C₁₋₆ alkyl such as acetoxymethyl andpivaloyloxymethyl group; (iii) a sulfonate group; (iv) sulfonamide groupoptionally substituted with a C₁₋₆ alkyl group or a C₆₋₁₀ aryl-C₁₋₄alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,benzyl, etc.); (v) hydroxy group and a sulfhydryl group, each optionallyalkylated with a C₁₋₃ alkyl group (e.g., methyl, ethyl, propyl, etc.);(vi) a carbamoyl group; (vii) phenyl group optionally substituted with 1to 5 substituents [e.g. a hydroxy group, chlorine, fluorine, anaminosulfonyl group, and amino group optionally substituted with a C₁₋₃alkyl group (e.g. methyl, ethyl, propyl, etc.)], and may be attached tothrough O or S; (viii) amino group optionally mono- or di-substitutedwith a C₁₋₃ alkyl group (e.g. methyl, ethyl, propyl, etc.); (ix) cyclicamino group optionally substituted with 1 to 3 C₁₋₃ alkyl group (e.g.,methyl, ethyl, etc.), benzyl, phenyl, and the like (e.g. a 5- to6-membered cyclic amino group which may contain an oxygen atom or asulfur atom in addition to a nitrogen atom as an annular atom of thecyclic amino group derived from a cyclic amine (by removing a hydrogenatom) such as piperidine, pyrrolidine, morpholine, thiomorpholine,piperazine, 4-methylpiperazine, 4-benzylpiperazine, 4-phenylpiperazine,1,2,3,4-tetrahydroisoquinoline, phthalimide, etc.); (x) a 5- to6-membered aromatic heterocyclic group (e.g., pyridyl, imidazolyl,indolyl, tetrazolyl, etc.) which may contain 1 to 4 hetero atomsselected from N, O or S, and may be attached to through O or S; (xi) ahalogen atom (e.g., chlorine, fluorine, bromine, iodine, etc.); (xii) anC₁₋₄ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, etc.), C₁₋₄ alkoxy group (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, t-butoxy, etc.) or C₁₋₄ alkylthio group (e.g.,methylthio, ethylthio, propylthio, isopropylthio, butylthio,tert-butylthio, etc.), each optionally substituted with substituentsselected from a C₁₋₄ alkoxy group, a C₁₋₄ alkylthio group, a carboxylgroup or a phenyl group; (xiii) a C₅₋₇ cycloalkyl group (e.g.,cyclopentyl, cyclohexyl, cycloheptyl, etc.); and (xiv) a C₁₋₇alkanoyloxy (e.g., formyloxy, acetoxy, propionyloxy, butyryloxy,t-butoxycarbonyloxy, isobutyryloxy, valeryloxy, pivaloyloxy, etc.).These substituents may be substituted at 1 to 6, preferably 1 to 3substitutable positions. In addition, two substituents may be bonded soas to form C₃₋₆ alkylene, C₃₋₆ alkyleneoxy, C₃₋₆ alkylenedioxy or thelike, for example, when two adjacent substituents on a phenyl group arebonded to form C₄ alkylene, tetrahydronaphthalene group is formed.

Specific examples of the group represented by—X^(1c)—X^(2c)—Ar—X^(3c)—X^(4c)—COOH in R^(1c) include an optionallysubstituted (carboxy-heteroaryl)-C₁₋₄ alkyl group [preferably, anoptionally substituted (carboxy-furyl)-C₁₋₄ alkyl group], an optionallysubstituted (carboxy-C₆₋₁₀ aryl-C₁₋₄ alkyl group), an optionallysubstituted carboxy-heteroaryl group, an optionally substitutedcarboxy-C₆₋₁₀ aryl group, an optionally substituted (carboxy-C₁₋₄alkyl)-heteroaryl group, an optionally substituted (carboxy-C₁₋₄alkyl)-C₆₋₁₀ aryl group [preferably, a (carboxy-C₂₋₃ alkyl)-C₆₋₁₀ arylgroup], an optionally substituted (carboxy-C₁₋₄ alkyl)-heteroaryl-C₁₋₄alkyl group, an optionally substituted (carboxy-C₁₋₄ alkyl)-C₇₋₁₄aralkyl group [preferably, a (carboxy-C₁₋₃ alkyl)-C₇₋₁₄ aralkyl group],an optionally substituted (carboxy-C₁₋₄ alkoxy)-C₆₋₁₀ aryl group, anoptionally substituted (carboxy-C₁₋₄ alkoxy)-C₆₋₀ aryl-C₁₋₄ alkyl group,an optionally substituted (carboxy-C₁₋₄ alkyl)-C₆₋₀ aryloxy-C₁₋₄ alkylgroup, an optionally substituted (carboxy-C₆₋₁₀ aryloxy)-C₁₋₄ alkylgroup and an optionally substituted (carboxy-C₁₋₄ alkylthio)-heteroarylgroup.

Herein, the same group as the aforementioned “aromatic heterocyclicgroup” may be exemplified for heteroaryl, and the heteroaryl may havethe same substituent as the substituent which the aforementioned“aromatic heterocyclic group” may have. In addition, examples of C₆₋₁₀aryl include phenyl, naphthyl, azulenyl, with phenyl being preferablyused. The C₆₋₁₀ aryl may have the same substituent as the substituentwhich the aforementioned “aromatic heterocyclic group” may have.Examples of the alkyl group in the optionally substituted(carboxyfuryl)-C₁₋₄ alkyl group represented by R¹ include, for example,C₁₋₄ linear or branched alkyl group such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, 1,1-dimethylethyl, and the like. Amongthese, a C₁₋₄ alkyl group such as methyl, ethyl, n-propyl, isopropyl andn-butyl are preferable, and methyl, ethyl, n-propyl are more preferable.Examples of the carboxyfuryl group include, for example,3-carboxy-2-furyl, 4-carboxy-2-furyl, 2-carboxy-3-furyl,2-carboxy-5-furyl. Among these, 3-carboxy-2-furyl and 4-carboxy-2-furylare preferable, and 3-carboxy-2-furyl is more preferable.

Examples of the C₂₋₃ alkyl group in the optionally substituted(carboxy-C₂₋₃ alkyl)-C₆₋₁₀ aryl group represented by R^(1c) includeethyl, n-propyl, isopropyl, with ethyl and n-propyl being preferable.Examples of the C₆₋₁₀ aryl group include phenyl, naphthyl, azulenyl,with phenyl being preferable.

Examples of the C₁₋₃ alkyl group in the optionally substituted(carboxy-C₁₋₃ alkyl)-C₇₋₁₄ aralkyl group represented by R^(1c) includemethyl, ethyl, n-propyl and isopropyl, with methyl and ethyl beingpreferable and ethyl being particularly preferable. Examples of a C₇₋₁₄aralkyl group (a C₆₋₁₀ aryl-C₁₋₄ alkyl group) include phenylmethyl,1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl,4-phenylbutyl, (1-naphthyl)methyl, (2-naphthyl)methyl,1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 3-(1-naphthyl)propyl,3-(1-naphthyl)propyl, 4-(1-naphthyl)butyl, 4-(2-naphthyl)butyl, withphenylmethyl, 1-phenylethyl, 3-phenylpropyl, (1-naphthyl)methyl,(2-naphthyl)methyl, (1-naphthyl) ethyl and (2-naphthyl) ethyl beingpreferable, and phenylmethyl and 2-phenylethyl being particularlypreferable.

As for the substituent, in the case each group represented by R^(1c)have a substituent, the same substituent as that “divalent aromaticheterocyclic group”, in the “optionally substituted divalent aromaticheterocyclic group” represented by Ar, may have is exemplified, andthese substituents can exist on 1 to 6, preferably 1 to 3 substitutablepositions. For each group represented by R^(1c) it is preferable thatthe carboxylic portion is unsubstituted, and an arbitrary portion otherthan the carboxylic portion may have a substitutable substituent at asubstitutable position.

As for R^(1c), a 3-carboxypropyl group, a 1-carboxyethyl group, or aC₃₋₆ linear alkyl-sulfonyl group, a (carboxy-C₅₋₇ cycloalkyl)-C₁₋₃ alkylgroup, a (carboxyfuryl)-alkyl group, a carboxy-C₆₋₁₀ aryl group, a(carboxy-C₁₋₄ alkyl)-C₆₋₁₀ aryl group [preferably, a (carboxy-C₂₋₃alkyl)-C₆₋₁₀ aryl group], or a (carboxy-C₁₋₃ alkyl)-C₇₋₁₄ aralkyl group,each of which may have substituent and the like are preferable, anoptionally substituted (carboxy-C₁₋₄ alkyl)-C₆₋₁₀ aryl group ispreferable, and an optionally substituted (carboxy-C₂₋₃ alkyl)-C₆₋₁₀aryl group is more preferable. Among these, an optionally substituted(carboxy-C₂₋₃ alkyl) phenyl group is preferable.

Examples of the C₃₋₆ alkyl group in the C₃₋₆ alkyl group optionallysubstituted with an alkanoyloxy group or a hydroxy group represented byR^(2c), include n-propyl, isopropyl, 1,1-dimethylethyl, n-butyl,isobutyl, n-pentyl, 2,2-dimethylpropyl, isopentyl, n-hexyl, isohexyl.Among these, isopropyl, 1,1-dimethylethyl, n-butyl, isobutyl,2,2-dimethylpropyl, isohexyl are preferable, and 2,2-dimethylpropyl isparticularly preferable.

Examples of the alkanoyloxy group in the C₃₋₆ alkyl group optionallysubstituted with an alkanoyloxy group or a hydroxy group represented byR^(2c) include a C₁₋₂₀ alkanoyloxy group such as formyloxy, acetoxy,propionyloxy, butyryloxy, tert-butoxycarbonyloxy, isobutyryloxy,valeryloxy, pivaloyloxy, lauryloxy, palmitoyloxy, stearoyloxy(preferably a C₁₋₇ alkanoyloxy group, etc.). Among these, acetoxy,propionyloxy, tert-butoxycarbonyloxy, palmitoyloxy are preferable, andacetoxy is particularly preferable. 1 to 3 of the alkanoyloxy groups orthe hydroxy groups may be substituted at a substitutable position.

Preferable examples of C₃₋₆ alkyl group optionally substituted with analkanoyloxy group or a hydroxy group represented by R^(2c) include, forexample, 2,2-dimethylpropyl, 3-hydroxy-2,2-dimethylpropyl,3-hydroxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2,2-dimethylpropyl,3-acetoxy-2-hydroxymethyl-2-methylpropyl and3-acetoxy-2-acetoxymethyl-2-methylpropyl. Among these,2,2-dimethylpropyl, 3-hydroxy-2,2-dimethylpropyl,3-acetoxy-2,2-dimethylpropyl is particularly preferable.

In addition, as R^(2c) a C₃₋₆ alkyl group having an alkanoyloxy groupand/or a hydroxy group is preferable.

Examples of the lower alkyl group represented by R^(3c) include a C₁₋₆alkyl group such as methyl; ethyl, n-propyl, isopropyl, n-butyl,tert-butyl, pentyl, hexyl. Among these, a C₁₋₃ alkyl group ispreferable. In view of the pharmacological activity, a methyl group isparticularly preferable as R^(3c).

Examples of the halogen atom represented by W include chlorine,fluorine, bromine and iodine atoms. Among these, a chlorine atom ispreferable.

The present invention includes the compound represented by the formula(Ic) in the form of either free or a pharmacologically acceptable saltthereof. As such salt, when the compound represented by the formula (Ic)has an acidic group such as a carboxyl group or the like, it may form asalt with an inorganic base (e.g., alkali metals such as sodium andpotassium, alkaline earth metals such as calcium and magnesium,transition metals such as zinc, iron and copper, etc.) or an organicbase (e.g., organic amines such as trimethylamine, triethylamine,pyridine, picoline, ethanolamine, diethanolamine, triethanolamine,dicyclohexylamine, N,N′-dibenzylethylenediamine, and basic amino acidssuch as an arginine, lysine, ornithine, etc.).

In the case where the compound represented by the formula (Ic) of thepresent invention has a basic group such as an amino group or the like,it may form a salt with inorganic or organic acid (e.g., hydrochloricacid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid,bicarbonic acid, formic acid, acetic acid, propionic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, etc.), acidic amino acidsuch as aspartic acid, glutamic acid, and the like.

The compound represented by the formula (Ic) or salts thereof hasasymmetric carbon atoms at 3- and 5-position, but they may be in amixture of the steroisomers, and the isomers may also be separated byconventional means. The trans isomer wherein the substituents on 3- and5-positions exist in the opposite direction relative to the surface of a7-membered ring, is preferable, and the isomer wherein the absoluteconfiguration at 3-position being R-configuration, and the absoluteconfiguration at 5-position being S-configuration is particularlypreferable. They may also be in a racemic or optically active form. Theoptically active form can be separated from the racemic form by theconventional optical resolution means.

As the compounds represented by the formula (Ic) and salts thereof ofthe present invention, the following compounds are preferablyexemplified.

N-propanesulfonyl-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetamideor salts thereof;(2R)-2-[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]aminopropionicacid or salts thereof;3-[3-[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]aminophenyl]propionicacid or salts thereof;4-[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]aminobutanoicacid or salts thereof;trans-4-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]-aminomethyl-1-cyclohexanecarboxylic acid or salts thereof;trans-4-[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]-aminomethyl-1-cyclohexanecarboxylicacid or salts thereof;3-[3-[[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]amino]-4-fluorophenyl]propionicacid or salts thereof;3-[3-[[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]amino]-4-methylphenyl]propionicacid or salts thereof;3-[3-[[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]amino]-4-methylphenyl]propionicacid or salts thereof;3-[3-[[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]aminomethyl]phenyl]propionicacid or salts thereof;3-[3-[[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]aminomethyl]phenyl]propionicacid or salts thereof;3-[3-[[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]amino]-4-methoxyphenyl]propionicacid or salts thereof;2-[2-[[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]amino]ethyl]furan-3-carboxylicacid or salts thereof;3-[3-[[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]amino]-4-fluorophenyl]propionicacid or salts thereof;3-[3-[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]aminophenyl]propionicacid or salts thereof;4-[3-[[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]amino]-4-methoxyphenyl]butanoicacid or salts thereof;5-[3-[[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]amino]-4-methoxyphenyl]pentanoicacid or salts thereof;5-[3-[[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]amino]-4-fluorophenyl]pentanoicacid or salts thereof.

The compound represented by the above-mentioned formula (Ic) or a saltthereof can be produced, for example, according to a method disclosed inEP A 567,026, WO95/21834 (international application based on JapanesePatent Application No. 6-15531), EP A 645,377 (application based onJapanese Patent Application No. 6-229159), EP A 645,378 (applicationbased on Japanese Patent Application No. 6-229160), WO01/98282(international application based on Japanese Patent Application No.2000-190253) and the like, or an equivalent method.

As the starting compound of the compound represented by the formula (I)of the present invention, the salts as mentioned above can be used, butthey are not particularly limited as long as they do not interfere withthe reaction.

The “skeletal muscle protection” in the present invention refers totherapeutic or preventive effects for the symptoms that the skeletalmuscle is in necrosis or myolysis caused by various factors, forexample, ischemia, labor, excessive exercise, trauma (bruise, skeletalmuscle bleeding, electric shock), burn, malignant hyperthermia,malignant syndrome, metabolic myopathy, inflammatory myopathy, musculardystrophy, infection, poisoning, abnormal metabolism, hyperthermia andthe like. More specifically, it refers to an action of protectingskeletal muscle from cell disorder caused by these factors (skeletalmuscle protecting action based on suppression of the cell disordercaused by these factors). Furthermore, it also comprises therapeutic orpreventive effects for myalgia by cytotoxicity of other medicines (forexample, an HMG-CoA reductase inhibitor, cyclosporin, fibrate-relatedmedicine and the like), and rhabdomyolysis as further serious case.

Particularly, the agent of the present invention shows excellenttherapeutic or preventive effects for myalgia, and further seriousrhabdomyolysis which are developed by an HMG-CoA reductase inhibitor,and suppresses the decrease of a geranylgeranylated metabolite (forexample, geranylgeranyl pyrophosphate, geranylgeraniol,geranylgeranylated protein and the like) in a muscular cell, which iscaused by the HMG-CoA reductase inhibitor. Herein, the HMG-CoA reductaseinhibitor includes atorvastatin, lovastatin, simvastatin, pravastatin,rosuvastatin, itavastatin, fluvastatin, cerivastatin, and pitavastatin

The agent of the present invention has an excellent skeletal muscleprotecting action, and further is low toxic and safe (for example, moreexcellent as a drug in view of acute toxicity, chronic toxicity, genetictoxicity, cardiac toxicity, drug interaction, carcinogenicity and thelike). Accordingly, the agent of the present invention can be usedsafely as, for example, a preventive and/or therapeutic agent forrhabdomyolysis, a preventive and/or therapeutic agent for myoglobinuriaaccompanied with rhabdomyolysis, a preventive and/or therapeutic agentfor myalgia and the like in a mammal (for example, mouse, rat, hamster,rabbit, cat, dog, cattle, horse, sheep, monkey, human and the like)

In the agent of the present invention, the compound having inhibitoryactivity against squalene synthase or a salt thereof, or a prodrugthereof (hereinafter, also referred to as an “SSI compound or a prodrugthereof”) which is an active ingredient, can be administered as bulkpowder, or usually in the form of a pharmaceutical composition orpreparation which is prepared by a conventional method usingconventional carriers for formulation in suitable amount, which carriersare suitably selected from, for example, an excipient (for example,calcium carbonate, kaolin, sodium hydrogen carbonate, lactose, starches,crystalline cellulose, talc, granulated sugar, porous substances, etc.),a binder (for example, dextrin, gums, alcoholized starch, gelatin,hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, etc.), adisintegrating agent (for example, carboxymethylcellulose calcium,sodium croscarmellose, crospovidone, low-substitutedhydroxypropylcellulose, partially pregelatinated starch, etc.), alubricant (for example, magnesium stearate, calcium stearate, talc,starch, sodium benzoate, etc.), a colorant (for example, tar dye,caramel, iron sesquioxide, titanium oxide, riboflavins, etc.), aflavoring substance (for example, sweeters, flavors, etc.), a stabilizer(for example, sodium sulphite, etc.), a preservative (for example,parabens, sorbic acid, etc.) and the like. The agent of the presentinvention including the above-mentioned preparations contains suitablythe SSI compound or prodrug thereof in an effective amount for treatingand preventing the diseases. The content of the SSI compound or prodrugthereof in the preparation of the present invention, is usually 0.1 to100% by weight based on the total preparation. Furthermore, thepreparation used in the present invention may contain other drugingredients as active ingredients, in addition to the SSI compound orprodrug thereof. Such ingredient is not particularly limited as long asthe object of the present invention is achieved, and can be used in asuitable mixing ratio. Specific examples of the preparations includetablets (including sugar-coated tablets and film-coated tablets), pills,capsules, granules, fine-granules, powders, syrup, emulsion, suspension,injectable preparation, sustained release injectable preparation,inhalant, ointment, etc. These preparations are prepared by aconventional method (for example, a method described in JapanesePharmacopoeia).

Specifically, tablets can be prepared by granulating suitably the SSIcompound or a prodrug thereof as it is, or with an excipient, a binder,a disintegrating agent, or other suitable additives, which are added andhomogenously kneaded, and then compressing and molding it with adding alubricant and the like. Alternatively, tablets can be prepared bydirectly compressing and molding the SSI compound or a prodrug thereofas it is, or with an excipient, a binder, a disintegrating agent, orother suitable additives, which are added and homogenously kneaded, orby compressing and molding granules previously prepared as they are, orwith suitable additives, which are added and homogenously kneaded.Furthermore, the present preparation can contain a colorant, a flavoringsubstance and the like, if necessary. Furthermore, the presentpreparation can be coated with a suitable coating agent. The injectablepreparation can be prepared by dissolving, suspending or emulsifying acertain amount of the SSI compound or a prodrug thereof in an aqueoussolvent such as an injectable solvent, a physiological saline solution,a Ringer's solution and the like, or in a non-aqueous solvent such as avegetable oil usually, to prepare a certain amount of the injectablesolution, or, by sealing a certain amount of the SSI compound or aprodrug thereof in a vessel for injection.

Carriers for oral preparations include substances conventionally used inthe field of a formulation such as starch, mannitol, crystallinecellulose and carboxymethylcellulose sodium. Carriers for injectioninclude, for example, distilled water, a physiological saline solution,a glucose solution, infusion solution and the like. Other additiveswhich are used for general formulations can be suitably added.

Furthermore, the preparation of the present invention can be used as asustained-release preparation. The sustained-release preparation can beadministered as microcapsules (for example, microsphere/microcapsules,micro-particles and the like) as they are, which are prepared by amethod such as drying-in-water method (o/w method, w/o/w method and thelike), phase separation method, spray drying method or a similar methodthereto, or as other various preparations formulated starting from apharmaceutical composition in the form of microcapsules, or spheres,needles, pellets, film or cream. The dosage form includes parenteralpreparations (for example, an injectable preparation or an implant forintramuscular, subcutaneous, organ; an intramucosal preparation fornasal cavity, rectum, uterus and the like), oral preparations (forexample, hard capsules, soft capsules, granules, powders, suspension andthe like) and the like.

When the sustained-release preparation is an injectable preparation, itis prepared as an aqueous suspension prepared by dispersingmicrocapsules with a dispersant (for example, a surfactant such as Tween80 and HCO-60; polysaccharide such as carboxymethylcellulose, sodiumalginate and sodium hyaluronate; protamine sulfate, polyethylene glycoland the like), a preservative (for example, methylparaben, propylparabenand the like), an isotonic agent (for example, sodium chloride,mannitol, sorbitol, glucose and the like), a local anesthetic (forexample, xylocalne hydrochloride, chlorobutanol and the like), or as anoily suspension prepared by dispersing them in a vegetable oil (forexample, sesame oil, corn oil and the like) or in a mixture thereof withphospholipid (for example, lecithin and the like), or with middle chaintriglyceride (for example, Miglyol 812 and the like).

When the sustained-release preparation is microcapsules, the meanparticle diameter is about 0.1 to about 300 μm, preferably, about 1 toabout 150 μm, more preferably about 2 to about 100 μm.

A method of preparing the microcapsules aseptic preparations includes amethod wherein all the processes are conducted under aseptic conditions,sterilization with gamma rays, the addition of an antiseptic and thelike, which are not particularly limited thereto.

Dose of the agent of the present invention is varied depending on anadministration route, symptoms, the age or body weight of the patientand the like. For example, when orally administered to an adult patientas a skeletal muscle protecting agent, it is preferable to administer 1to 400 mg/day, preferably 6 to 120 mg/day as the SSI compound once orseveral times a day. The administration route may be oral or parenteral.

Furthermore, the dose of the sustained-release preparation as an exampleof the agent of the present invention is varied depending on theduration of release as well as the administration route, symptoms, theage or weight of the patient and the like. However, it is notparticularly limited if it is an amount to maintain the effectiveconcentration of the active ingredient in the body and the number ofadministration can be suitably selected depending on the situation, forexample, once a day to once 3 days, or once a week to once 3 months.

When the skeletal muscle protecting agent of the present invention isused for protecting skeletal muscle from cytotoxicity of an HMG-CoAreductase inhibitor, the administration mode of the SSI compound and theHMG-CoA reductase inhibitor used in the present invention is notparticularly limited, and the SSI compound and the HMG-CoA reductaseinhibitor may be combined at the time of administration. Examples ofsuch administration mode include the following methods:

-   -   (1) administration of a single preparation prepared by        formulating the SSI compound and the HMG-CoA reductase inhibitor        simultaneously (2) simultaneous administration of two kinds of        preparations obtained by formulating the SSI compound and the        HMG-CoA reductase inhibitor separately, via a single        administration route, (3) separate administration at an interval        of two kinds of preparations obtained by formulating the SSI        compound and the HMG-CoA reductase inhibitor separately, via a        single administration route, (4) simultaneous administration of        two kinds of preparations obtained by formulating the SSI        compound and the HMG-CoA reductase inhibitor separately, via        different administration routes, (5) separate administration at        an interval of two kinds of preparations obtained by formulating        the SSI compound and the HMG-CoA reductase inhibitor separately,        via different administration routes (e.g. administration of the        SSI compound followed by the HMG-CoA reductase, or        administration in the reverse order). Dose of an HMG-CoA        reductase inhibitor can be appropriately selected based on the        dose which is clinically used. The compounding ratio of the SSI        compound and an HMG-CoA reductase inhibitor can be appropriately        selected depending on the administration subject, administration        route, target diseases, symptoms, combinations thereof, etc. For        example, if the administration subject is human, the SSI        compound may be used in an amount of 0.01 to 100 parts by weight        to 1 part by weight of the HMG-CoA reductase inhibitor.

The agent of the present invention has an excellent skeletal muscleprotecting action, and for example, it has excellent preventive and/ortherapeutic effects for myalgia or rhabdomyolysis which is developed byother medicines such as the HMG-CoA reductase inhibitor.

Hereinafter, test results showing the pharmacological effects of theagent of the present invention are described.

Test Compound 1:

-   N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic    acid

Test compound 1 is a compound described in Example 36 of JP-A No.2002-080468, and can be synthesized by the method described in thispublication and the like.

Test Compound 2:

-   3-[3-[[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]amino]phenyl]propionic    acid

Test compound 2 is a compound described in Example 36 of JP-A No.9-136880, and can be synthesized by the method described in thispublication and the like. Furthermore, it has been described in Test 1of the publication that the test compound 2 has inhibitory activityagainst squalene synthase.

Test Compound 3:

-   N-[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic    acid

Test compound 3 is a compound described as compound No. 13-1 in JP-A No.9-136880, and can be synthesized by the method described in thispublication and the like. Furthermore, it has been described in Test 1of the publication that the test compound 3 has inhibitory activityagainst squalene synthase.

TEST EXAMPLE 1

Increasing Effect on Geranylgeraniol (GGOH) Content in Soleus Muscle

Method:

To 6 week-old male SD rat (4 per group) was orally administered forcedlyby means of a stomach sonde a vehicle or Test compounds 1 or 2 at a doseof 10 mL/kg once a day for 14 days so as to be in an amount of 40 or 200mg/kg. In the next morning of the 14th administration, the rat waskilled under ether anesthesia. Immediately, the soleus muscle wascollected and frozen on a dry ice, and then kept at −80° C. Later, tothe muscle homogenate was added phosphatase for dephosphorylation, andthen the concentration of geranylgeraniol (sum total of geranylgeranylpyrophosphate and geranylgeraniol) in the muscle was determined withLC/MS/MS (Table 1).

Results: TABLE 1 GGOH content in the Dose soleus muscle Treatment(mg/kg) (μg/g soleus muscle) Vehicle 0 0.190 ± 0.007 Test 40 0.224 ±0.017 compound 1 Test 200 0.255 ± 0.027* compound 1 Test 40 0.225 ±0.019 compound 2 Test 200 0.255 ± 0.006* compound 2Data represent Mean ± SE (N = 4).*P < 0.025 vs. Control (one-tailed Williams' test)

Results of Table 1 showed that the SSI compound increased thegeranylgeraniol content in the skeletal muscle.

TEST EXAMPLE 2

Effect of Geranylgeranyl Pyrophosphate (GGPP) on Cytotoxicity of HMG-CoAReductase Inhibitor

Method:

Human normal skeletal muscle cells (Bio Whittaker) having passage number6 were cultured on a 96-well plate in a SkGM medium (Bio Whittaker), andwere divided into Groups 1 to 6 shown in Table 1 in a confluent state.The drugs in Treatments 1 and 2 were added at the same time, and after 3days, the content of ATP in the cell was measured with an ATP Lite-M kit(Packard), and the number of live cells was measured (Table 2).

Results: TABLE 2 The number of Treatment the live cells Treatment 1 2 (%of Group 1) Group 1 Vehicle Vehicle  100 ± 1.3 Group 2 Vehicle GGPP (1093.5 ± 0.8 μM) Group 3 Simvastatin (10 μM) Vehicle 46.2 ± 1.5# Group 4Simvastatin (10 μM) GGPP (10 72.3 ± 1.6* μM) Group 5 Atorvastatin (10Vehicle 52.0 ± 0.9# μM) Group 6 Atorvastatin (10 GGPP (10 67.8 ± 1.3$μM) μM)Data represent Mean ± SE (N = 3).#P < 0.025 vs Group 1 (one-tailed Williams' test)*P < 0.01 vs Group 3 (Student's t test)$P < 0.01 vs Group 5 (Student's t test)

Results of Table 2 showed that geranylgeranyl pyrophosphate, which is anactive form of geranylgeraniol in the living body that is increased bythe SSI compound, had an activity reducing cytotoxicity in skeletalmuscle cells.

TEST EXAMPLE 3

Effect of Test Compound 3 on Cytotoxicity of HMG-CoA Reductase Inhibitor(1)

Method:

Human normal skeletal muscle cells (Bio Whittaker) having passage number6 were cultured on a 96-well plate in a SkGM medium (Bio Whittaker), andwere divided into Groups 1 to 4 shown in Table 3 as a confluent state.The drugs in Treatments 1 and 2 were added at the same time, and after 3days, the content of ATP in the cell was measured with an ATP Lite-M kit(Packard), and the number of the live cells was measured (Table 3).

Results: TABLE 3 The number of the live cells Treatment 1 Treatment 2 (%of Group 1) Group 1 Vehicle Vehicle 100 ± 3.6 Group 2 Test compoundVehicle  96 ± 1.2 3 (10 μM) Group 3 Vehicle Atorvastatin (100  34 ± 0.6#μM) Group 4 Test compound Atorvastatin (100  42 ± 0.5* 3 (10 μM) μM)Data represent Mean ± SE (N = 3).#P < 0.025 vs Group 1 (one-tailed Williams' test)*P < 0.05 vs Group 3 (Student's t test)

TEST EXAMPLE 4

Effect of Test Compound 3 on Cytotoxicity of HMG-CoA Reductase Inhibitor(2)

Method:

Human normal skeletal muscle cells (Bio Whittaker) having passage number6 were cultured on a 96-well plate in a SkGM medium (Bio Whittaker), andwere divided into Groups 1 to 6 shown in Table 4 as a confluent state.The drug in Treatment 1 was added and after 1 day, the medium wascompletely removed. Then, the drug in Treatment 2 was added and after 3days, the content of ATP in the cell was measured with an ATP Lite-M kit(Packard), and the number of the live cells was measured (Table 4).

Results: TABLE 4 The number of the live cells Treatment 1 Treatment 2 (%of Group 1) Group 1 Vehicle Vehicle 100 ± 0.5 Group 2 Test compound 3Vehicle  98 ± 2.3 (10 μM) Group 3 Vehicle Atorvastatin (10  57 ± 1.1#μM) Group 4 Test compound 3 Atorvastatin (10  76 ± 1.8** (10 μM) μM)Group 5 Vehicle Atorvastatin (100  35 ± 1.9# μM) Group 6 Test compound 3Atorvastatin (100  45 ± 0.2* (10 μM) μM)Data represent Mean ± SE (N = 3).#P < 0.025 vs Group 1 (one-tailed Williams' test)**P < 0.01 vs Group 3 (Student's t test)*P < 0.05 vs Group 5 (Student's t test)

The results of Tables 3 and 4 showed that the SSI compound had anexcellent activity reducing cytotoxicity in atorvastatin-treatedskeletal muscle cells.

PREPARATION EXAMPLE

The skeletal muscle protecting agent of the present invention can beproduced, for example, by the following prescription.

In addition, for ingredients other than the active ingredients(additives) described in the following prescription, products describedin Japanese Pharmacopoeia, Japanese Pharmaceutical Codex, or TheJapanese Standards of Drug Additives can be used.

1. Capsule (1) N-[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3- 10 mghydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid (2) Lactose 90 mg (3)Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule180 mg 

(1), (2) and (3) and the half of (4) are kneaded and then granulated. Tothis is added the remaining (4), and the whole is sealed into a gelatincapsule.

2. Tablet (1) N-[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3- 10 mghydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid (2) Lactose 35 mg (3)Corn starch 150 mg  (4) Microcrystalline cellulose 30 mg (5) Magnesiumstearate  5 mg 1 tablet 230 mg 

(1), (2), (3), 2/3 of (4) and the half of (5) are kneaded and thengranulated. The remaining (4) and (5) are added to the granules, andcompressed and molded into tablets.

3. Injection (1) N-[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-  10mg hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid (2) Inositol 100 mg(3) Benzyl alcohol  20 mg 1 Ampoule 130 mg

(1), (2) and (3) are dissolved in distilled injection solvent so as tobe a total of 2 ml, which is sealed into an ampoule. All steps areconducted under sterilized conditions.

INDUSTRIAL APPLICABILITY

The agent of the present invention has an excellent skeletal muscleprotecting action, and for example, it has excellent preventive and/ortherapeutic effects for myalgia or rhabdomyolysis which is developed byother medicines such as an HMG-CoA reductase inhibitor.

1. A skeletal muscle protecting agent comprising a compound havinginhibitory activity against squalene synthase or a salt thereof, or aprodrug thereof.
 2. The agent according to claim 1, which is a skeletalmuscle protecting agent which protects skeletal muscle from celldisorder.
 3. The agent according to claim 1, which is a skeletal muscleprotecting agent which protects skeletal muscle from cytotoxicity ofother medicines.
 4. The agent according to claim 3, wherein the othermedicine is an HMG-CoA reductase inhibitor.
 5. The agent according toclaim 1, which is a preventive and/or therapeutic agent for myalgia orrhabdomyolysis.
 6. The agent according to claim 1, wherein the compoundhaving inhibitory activity against squalene synthase is a compoundrepresented by the formula:

wherein R₁ is a hydrogen atom or an optionally substituted hydrocarbongroup, R₂ and R₃ are the same or different and a hydrogen atom, anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group, X′ is a substituent comprising an optionallyesterified carboxyl group, an optionally substituted carbamoyl group, anoptionally substituted hydroxy group, an optionally substituted aminogroup or an optionally substituted heterocyclic residue having ahydrogen atom which can be deprotonated, Ring A is an optionallysubstituted benzene ring or an optionally substituted heterocyclic ring,Ring J′ is a 7- or 8-membered heterocyclic ring having 3 or less heteroatoms, as atoms constituting a ring, and Ring J′ may further have asubstituent in addition to R₁, R₂, R₃ and X′.
 7. The agent according toclaim 1, wherein the compound having inhibitory activity againstsqualene synthase is a compound represented by the formula:

wherein R₁ is a hydrogen atom or an optionally substituted hydrocarbongroup, R₂ and R₃ are the same or different and a hydrogen atom, anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group, X₁ is a bond or divalent atomic chain, Y is anoptionally esterified carboxyl group, an optionally substitutedcarbamoyl group, an optionally substituted hydroxy group, an optionallysubstituted amino group or an optionally substituted heterocyclicresidue having a hydrogen atom which can be deprotonated, and Ring B isan optionally substituted benzene ring.
 8. The agent according to claim1, wherein the compound having inhibitory activity against squalenesynthase is a compound represented by the formula:

wherein R_(b) is a lower alkyl group optionally substituted with anoptionally substituted hydroxy group, X_(b) is an optionally substitutedcarbamoyl group or an optionally substituted heterocyclic group having ahydrogen atom which can be deprotonated, R_(1b) is a lower alkyl groupand W is a halogen atom.
 9. The agent according to claim 8, whereinR_(b) is C₁₋₆ alkyl which may have 1 to 3 substituents selected from ahydroxy group, acetyloxy, propionyloxy, t-butoxycarbonyloxy,palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy.
 10. Theagent according to claim 8, wherein R_(1b) is methyl.
 11. The agentaccording to claim 8, wherein W is a chlorine atom.
 12. The agentaccording to claim 8, wherein X_(b) is a group represented by theformula:

wherein R_(2b) and R_(3b) are each a hydrogen atom, an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup or an acyl group, or R_(2b) and R_(3b) may form, together with theadjacent nitrogen atom, an optionally substituted 5- or 6-memberednitrogen-containing heterocyclic ring which may contain 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom,as atoms constituting a ring.
 13. The agent according to claim 8,wherein X_(b) is a group represented by the formula:

wherein R″ is a hydrogen atom or C₁₋₄ alkyl.
 14. The agent according toclaim 1, wherein the compound having inhibitory activity againstsqualene synthase isN-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-aceticacid orN-[[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-aceticacid.
 15. A skeletal muscle protecting agent comprising a compoundhaving an action of suppressing the decrease of a geranylgeranylatedmetabolite in a muscular cell, or a salt thereof, or a prodrug thereof.16. A method for protecting skeletal muscle, comprising administering aneffective amount of a compound having inhibitory activity againstsqualene synthase, or a salt thereof, or a prodrug thereof to a mammal.17. A method for protecting skeletal muscle, comprising administering aneffective amount of a compound having an action of suppressing thedecrease of a geranylgeranylated metabolite in a muscular cell, or asalt thereof, or a prodrug thereof to a mammal.
 18. Use of a compoundhaving inhibitory activity against squalene synthase, or a salt thereof,or a prodrug thereof for manufacturing a skeletal muscle protectingagent.
 19. Use of a compound having an action of suppressing thedecrease of a geranylgeranylated metabolite in a muscular cell, or asalt thereof, or a prodrug thereof for manufacturing a skeletal muscleprotecting agent.